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1. Structural basis of the human endoglin-BMP9 interaction: Insights into BMP signaling and HHT1

Author

Takako, Saito, Marcel, Bokhove, Romina, Croci, Sara, Zamora-Caballero, Ling, Han, Michelle, Letarte, Daniele, de Sanctis, Luca, Jovine, Karolinska Inst, Ctr Innovat Med, S-14183 Huddinge, Sweden, Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge, Sweden, Fukushima Med Univ, Sch Med, Inst Biomed Sci, Dept Cell Sci, Fukushima 9601295, Japan, Univ Toronto, Dept Immunol, Toronto, ON M5G 0A4, Canada, Univ Toronto, Hosp Sick Children, Peter Gilgan Ctr Res & Learning, Mol Med, Toronto, ON M5G 0A4, Canada, and European Synchrotron Radiation Facility (ESRF)

Subjects
Models, Molecular, Activin Receptors, Type II, [SDV]Life Sciences [q-bio], orphan domain, Crystallography, X-Ray, Ligands, Protein Structure, Secondary, Article, Structure-Activity Relationship, Protein Domains, Gene Duplication, Humans, hereditary hemorrhagic telangiectasia, protein interaction domains and motifs, Disulfides, lcsh:QH301-705.5, x-ray crystallography, endoglin, zona pellucida domain, bone morphogenetic protein receptors, cell surface receptors, TGF-β superfamily proteins, growth differentiation factor 2, Kinetics, lcsh:Biology (General), Telangiectasia, Hereditary Hemorrhagic, Protein Multimerization, Hydrophobic and Hydrophilic Interactions, Protein Binding, Signal Transduction
Abstract

Summary Endoglin (ENG)/CD105 is an essential endothelial cell co-receptor of the transforming growth factor β (TGF-β) superfamily, mutated in hereditary hemorrhagic telangiectasia type 1 (HHT1) and involved in tumor angiogenesis and preeclampsia. Here, we present crystal structures of the ectodomain of human ENG and its complex with the ligand bone morphogenetic protein 9 (BMP9). BMP9 interacts with a hydrophobic surface of the N-terminal orphan domain of ENG, which adopts a new duplicated fold generated by circular permutation. The interface involves residues mutated in HHT1 and overlaps with the epitope of tumor-suppressing anti-ENG monoclonal TRC105. The structure of the C-terminal zona pellucida module suggests how two copies of ENG embrace homodimeric BMP9, whose binding is compatible with ligand recognition by type I but not type II receptors. These findings shed light on the molecular basis of the BMP signaling cascade, with implications for future therapeutic interventions in this fundamental pathway., Graphical Abstract, Highlights • Crystal structures of human ENG and its complex with BMP9 were determined • The orphan domain of ENG adopts a fold that explains the effect of HHT1 mutations • ZP module-mediated dimerization of ENG creates a clamp that secures homodimeric BMP9 • ENG-bound BMP9 can interact with the ALK1 receptor but not the ActRIIB receptor, Endoglin (ENG)/CD105, a key player in angiogenesis and vascular homeostasis, is mutated in the genetic disorder HHT1 and implicated in tumor angiogenesis and preeclampsia. Saito et al. determine structures of human ENG alone and in complex with the physiological ligand BMP9, shedding light onto the molecular basis of BMP signaling.

Published
2017
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2. Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

Author

Javier Benitez, Marie Stenmark-Askmalm, Susan L. Neuhausen, Pascal Guénel, Jane Carpenter, Christine B. Ambrosone, Dominique Stoppa-Lyonnet, Nadine Tung, Gad Rennert, Stephen J. Chanock, Andrew K. Godwin, Regina M. Santella, Brita Arver, Karoline Kuchenbaecker, Kamila Czene, Vessela N. Kristensen, Natalia Bogdanova, Nazneen Rahman, Jianjun Liu, Federico Canzian, Hoda Anton-Culver, Maya Ghoussaini, Mark E. Robson, Sue K. Park, Manjeet K. Bolla, Roger L. Milne, Veli-Matti Kosma, Siranoush Manoukian, Angela Cox, Daniel F. Schmidt, Kay-Tee Khaw, Rosario Tumino, Melissa C. Southey, Ramunas Janavicius, Irene Konstantopoulou, Carl Blomqvist, John L. Hopper, Sue Healey, Christine Rappaport, Marco Montagna, SA Gayther, Heather Eliassen, Carolien H.M. van Deurzen, Jacques Simard, Emiel J. Rutgers, Jonine Figueroa, Maria A. Caligo, Volker Arndt, Sylvie Mazoyer, Diana Eccles, M.J. Hooning, Antoinette Hollestelle, Mary B. Daly, Robert Winqvist, Antonis C. Antoniou, Patricia A. Ganz, Orland Diez, Priyanka Sharma, Ana Osorio, Daniel Barrowdale, Loic Le Marchand, Drakoulis Yannoukakos, Elinor J. Sawyer, Conxi Lázaro, Soo-Hwang Teo, Penny Soucy, Paolo Radice, John W. M. Martens, Steve Ellis, David E. Goldgar, Anna Jakubowska, Maria Kabisch, Raymonda Varon-Mateeva, Diether Lambrechts, Paul D.P. Pharoah, Leigha Senter, Anna González-Neira, Cecilia M. Dorfling, Brian E. Henderson, Rulla M. Tamimi, Sara Margolin, Susan M. Gapstur, Ian Tomlinson, Thérèse Truong, Robert A.E.M. Tollenaar, Amanda E. Toland, Anna Marie Mulligan, Irene L. Andrulis, Isabelle Romieu, Monica Barile, Florentia Fostira, Johanna Rantala, Enes Makalic, Eitan Friedman, Zhaoming Wang, Mark H. Greene, Noralane M. Lindor, Julie M. Cunningham, Riccardo Dolcetti, Steven N. Hart, Mary Beth Terry, Jenny Chang-Claude, Austin Miller, Georgia Chenevix-Trench, Asta Försti, Kathleen E. Malone, Paolo Peterlongo, Lothar Haeberle, Celine M. Vachon, Elizabeth J. van Rensburg, Michael Jones, Laima Tihomirova, Penelope Miron, Eunjung Lee, María José Sánchez, Hatef Darabi, Frans B. L. Hogervorst, Matthias W. Beckmann, Edith Olah, Annika Lindblom, Phuong L. Mai, Emily Hallberg, Alison M. Dunning, Kathleen Claes, Esther M. John, Sofia Khan, David J. Hunter, Kristiina Aittomäki, Katherine L. Nathanson, Lars Beckmann, Stephanie V. Blank, Wei Zheng, Olufunmilayo I. Olopade, Heli Nevanlinna, Miguel de la Hoya, Olga M. Sinilnikova, Bruce Poppe, Catherine M. Phelan, S. Lindstrom, Stig E. Bojesen, Curtis Olswold, Fredrick R. Schumacher, Janet E. Olson, Tuomas Heikkinen, Judy Garber, Fergus J. Couch, Tara M. Friebel, Isabel dos-Santos-Silva, Douglas F. Easton, Song Yao, Dieter Flesch-Janys, Hans Ehrencrona, Simon S. Cross, Rodney J. Scott, Kenneth Offit, Petra H.M. Peeters, Clare Turnbull, Taru A. Muranen, William J. Tapper, Trinidad Caldés, Jenny Lester, Robert L. Nussbaum, Paul A. James, Marike Gabrielson, Susan M. Domchek, Mads Thomassen, Marilie D. Gammon, Susan L. Slager, Graham G. Giles, Silje Nord, Hans Wildiers, Hiltrud Brauch, Gustavo Mendoza-Fandiño, Christopher A. Haiman, Martine Dumont, Mark S. Goldberg, Bernardo Bonanni, Jirong Long, Kyriaki Michailidou, Ute Hamann, Wendy K. Chung, Marc J. Gunter, Mia M. Gaudet, Keith Humphreys, Per Hall, Yuan C. Ding, Simona Agata, Julia A. Knight, Robert Pilarski, Claudine Isaacs, Alvaro A.N. Monteiro, Montserrat Garcia-Closas, Rosa B. Barkardottir, Beth Y. Karlan, Uffe Birk Jensen, Arif B. Ekici, Evgeny N. Imyanitov, Alex Teulé, Anne-Marie Gerdes, Frederik Marme, Debra Frost, Anthony J. Swerdlow, Yon Ko, Xiaohong R. Yang, Jan Lubinski, Peter A. Fasching, Lesley McGuffog, Jacek Gronwald, Katri Pylkäs, Banu Arun, Josef Herzog, Gord Glendon, Doris Steinemann, Tomasz Huzarski, Peter Kraft, Anja Rudolph, Arto Mannermaa, Habibul Ahsan, Christian F. Singer, Rita K. Schmutzler, Julian Peto, Giski Ursin, Shan Wang-Gohrke, Andrea L. Richardson, Jeffrey N. Weitzel, Børge G. Nordestgaard, Marjanka K. Schmidt, Alice S. Whittemore, Hermann Brenner, Barbara Burwinkel, D Thompson, Csilla I. Szabo, M. Pilar Zamora, Janna Lilyquist, Muhammad G. Kibriya, Yael Laitman, Helen Tsimiklis, W. D. Foulkes, Thomas Hansen, Francesca Damiola, Robert N. Hoover, Ava Kwong, Alfons Meindl, Siddhartha Kar, Manuel R. Teixeira, Elisabete Weiderpass, Bernard Peissel, Saundra S. Buys, Peter Devilee, Unión Europea. Comisión Europea. 7 Programa Marco, Cancer Research UK (Reino Unido), National Institutes of Health (Estados Unidos), Canadian Institutes of Health Research, Florida Breast Cancer Foundation (Estados Unidos), Dunning, Alison [0000-0001-6651-7166], Ghoussaini, Maya [0000-0002-2415-2143], Khaw, Kay-Tee [0000-0002-8802-2903], Thompson, Deborah [0000-0003-1465-5799], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Medical Oncology, Obstetrics & Gynecology, Pathology, Cell biology, Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, Clinicum, Department of Oncology, Department of Obstetrics and Gynecology, HUS Gynecology and Obstetrics, and [ 1 ] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA [ 2 ] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA [ 3 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England [ 4 ] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Canc Epidemiol Program, Tampa, FL 33612 USA [ 5 ] Radiumhosp, Oslo Univ Hosp, Inst Canc Res, Dept Genet, N-0310 Oslo, Norway [ 6 ] IRCCS, IOV, Immunol & Mol Oncol Unit, I-20133 Padua, Italy [ 7 ] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA [ 8 ] Univ Chicago, Ctr Comprehens Canc, Chicago, IL 60637 USA [ 9 ] Univ Chicago, Dept Med & Human Genet, Chicago, IL 60637 USA [ 10 ] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki 00029, Finland [ 11 ] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA [ 12 ] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada [ 13 ] Univ Toronto, Dept Mol Genet, Toronto, ON M5B 1W8, Canada [ 14 ] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5B 1W8, Canada [ 15 ] Univ Calif Irvine, Dept Epidemiol, Irvine, CA 92697 USA [ 16 ] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, D-69120 Heidelberg, Germany [ 17 ] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA [ 18 ] Karolinska Univ Hosp, Dept Oncol, SE-17176 Stockholm, Sweden [ 19 ] Ist Europeo Oncol, Div Canc Prevent & Genet, I-20141 Milan, Italy [ 20 ] Landspitali Univ Hosp, Dept Pathol, IS-101 Reykjavik, Iceland Organization-Enhanced Name(s) Landspitali National University Hospital [ 21 ] Univ Iceland, Sch Med, IS-101 Reykjavik, Iceland [ 22 ] Inst Qual & Efficiency Hlth Care IQWiG, D-50670 Cologne, Germany [ 23 ] Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen EMN, Univ Breast Ctr Franconia, Dept Gynecol & Obstet,Univ Hosp Erlangen, D-91054 Erlangen, Germany [ 24 ] Spanish Natl Canc Ctr CNIO, Human Genet Grp, Human Canc Genet Program, Madrid 28029, Spain [ 25 ] Spanish Natl Canc Ctr CNIO, Human Canc Genet Program, Genotyping Unit CeGen, Madrid 28029, Spain [ 26 ] Biomed Network Rare Dis CIBERER, Madrid 28029, Spain [ 27 ] NYU, Sch Med, NYU Womens Canc Program, New York, NY 10016 USA [ 28 ] Univ Helsinki, Dept Oncol, FI-00029 Helsinki, Finland [ 29 ] Univ Helsinki, Cent Hosp, FI-00029 Helsinki, Finland [ 30 ] Hannover Med Sch, Dept Radiat Oncol, D-30625 Hannover, Germany [ 31 ] Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, DK-2730 Herlev, Denmark [ 32 ] Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-70376 Stuttgart, Germany [ 33 ] Univ Tubingen, D-72074 Tubingen, Germany [ 34 ] German Canc Res Ctr, Div Prevent Oncol, D-69120 Heidelberg, Germany [ 35 ] Natl Ctr Tumor Dis NCT, D-69120 Heidelberg, Germany [ 36 ] Heidelberg Univ, Dept Obstet & Gynecol, D-69120 Heidelberg, Germany [ 37 ] Univ Utah, Sch Med, Dept Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA [ 38 ] IdISSC, Hosp Clin San Carlos, Mol Oncol Lab, Madrid 28040, Spain [ 39 ] Univ Pisa, Dept Lab Med, Sect Genet Oncol, I-56126 Pisa, Italy [ 40 ] Univ Hosp Pisa, I-56126 Pisa, Italy [ 41 ] German Canc Res Ctr, Genom Epidemiol Grp, D-69120 Heidelberg, Germany [ 42 ] Univ Sydney, Westmead Millennium Inst, Australian Breast Canc Tissue Bank, Sydney, NSW 2145, Australia [ 43 ] German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany [ 44 ] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA [ 45 ] Columbia Univ, Dept Pediat, New York, NY 10032 USA [ 46 ] Columbia Univ, Dept Med, New York, NY 10032 USA [ 47 ] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium [ 48 ] Univ Sheffield, Dept Oncol, Sheffield Canc Res Ctr, Sheffield S10 2RX, S Yorkshire, England [ 49 ] Univ Sheffield, Acad Unit Pathol, Dept Neurosci, Sheffield S10 2HQ, S Yorkshire, England [ 50 ] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden [ 51 ] Fox Chase Canc Ctr, Dept Clin Genet, Philadelphia, PA 19111 USA [ 52 ] Univ Lyon, CNRS, UMR5286, Ctr Rech Cancerol Lyon,INSERM,U1052, F-69373 Lyon, France [ 53 ] Leiden Univ, Med Ctr, Dept Human Genet, NL-2333 ZC Leiden, Netherlands [ 54 ] Leiden Univ, Med Ctr, Dept Pathol, NL-2333 ZC Leiden, Netherlands [ 55 ] Univ Hosp Vall dHebron, VHIO, Oncogenet Grp, Barcelona 08035, Spain [ 56 ] Univ Autonoma Barcelona, Barcelona 08035, Spain [ 57 ] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA 91010 USA [ 58 ] CRO Aviano Natl Canc Inst, Canc Bioimmunotherapy Unit, I-33081 Aviano, Italy [ 59 ] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA [ 60 ] Univ Pretoria, Dept Genet, ZA-0007 Pretoria, South Africa [ 61 ] Univ London London Sch Hyg & Trop Med, Dept Non Communicable Dis Epidemiol, Keppel St, London WC1E 7HT, England [ 62 ] Ctr Hosp Univ Quebec, Canc Genom Lab, Quebec City, PQ G1V 4G2, Canada [ 63 ] Univ Laval, Quebec City, PQ G1V 4G2, Canada [ 64 ] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England [ 65 ] Univ Southampton, Southampton Univ Hosp, Fac Med, Southampton SO16 6YD, Hants, England [ 66 ] Uppsala Univ, Dept Immunol Genet & Pathol, SE-75185 Uppsala, Sweden [ 67 ] Univ Lund Hosp, Dept Clin Genet, SE-22185 Lund, Sweden [ 68 ] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Inst Human Genet, D-91054 Erlangen, Germany [ 69 ] Comprehens Canc Ctr EMN, D-91054 Erlangen, Germany [ 70 ] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA [ 71 ] Harvard Univ, Sch Med, Boston, MA 02115 USA [ 72 ] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA [ 73 ] Univ Clin Hamburg Eppendorf, Clin Canc Registry, Dept Canc Epidemiol, D-20246 Hamburg, Germany [ 74 ] Univ Clin Hamburg Eppendorf, Inst Med Biometr & Epidemiol, D-20246 Hamburg, Germany [ 75 ] German Canc Res Ctr, Div Mol Genet Epidemiol, D-69120 Heidelberg, Germany [ 76 ] Lund Univ, Ctr Primary Hlth Care Res, SE-22100 Malmo, Sweden [ 77 ] Natl Ctr Sci Res Demokritos, INRASTES, Mol Diagnost Lab, Athens 15310, Greece [ 78 ] McGill Univ, Program Canc Genet, Montreal, PQ H3A 0G4, Canada [ 79 ] Univ Philadelphia, Philadelphia, PA 19104 USA [ 80 ] Chaim Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, IL-52621 Tel Hashomer, Israel [ 81 ] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA [ 82 ] Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, UCLA Sch Med, Los Angeles, CA 90095 USA [ 83 ] Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, UCLA Sch Publ Hlth, Los Angeles, CA 90095 USA [ 84 ] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30303 USA [ 85 ] Dana Farber Canc Inst, Canc Risk & Prevent Clin, Boston, MA 02215 USA [ 86 ] Cedars Sinai Med Ctr, Dept Biomed Sci, Los Angeles, CA 90048 USA [ 87 ] Copenhagen Univ Hosp, Rigshosp, Dept Clin Genet, DK-2100 Copenhagen, Denmark [ 88 ] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic 3010, Australia [ 89 ] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66205 USA [ 90 ] McGill Univ, Dept Med, Montreal, PQ H3G 2M1, Canada [ 91 ] McGill Univ, Ctr Hlth, Royal Victoria Hosp, Div Clin Epidemiol, Montreal, PQ H4A 3J1, Canada [ 92 ] Univ Utah, Sch Med, Huntsman Canc Inst, Dept Dermatol, Salt Lake City, UT 84132 USA [ 93 ] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Human Genotyping CEGEN Unit, Madrid 28029, Spain [ 94 ] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA [ 95 ] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland [ 96 ] CESP Ctr Res Epidemiol & Populat Hlth, Inserm Natl Inst Hlth & Med Res, U1018, Environm Epidemiol Canc, F-70115 Villejuif, France [ 97 ] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London SW7 2AZ, England [ 98 ] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA [ 99 ] German Canc Res Ctr, Mol Genet Breast Canc, D-69120 Heidelberg, Germany [ 100 ] Copenhagen Univ Hosp, Rigshosp, Ctr Genom Med, DK-2100 Copenhagen, Denmark [ 101 ] QIMR Berghofer Med Res Inst, Dept Genet, Brisbane, Qld 4029, Australia [ 102 ] Univ Helsinki, Cent Hosp, FI-00029 Helsinki, Finland [ 103 ] City Hope Clin Canc Genet Community Res Network, Clin Canc Genet, Duarte, CA 91010 USA [ 104 ] Netherlands Canc Inst, Family Canc Clin, NL-1000 BE Amsterdam, Netherlands [ 105 ] Erasmus MC Canc Inst, Dept Med Oncol, NL-3008 AE Rotterdam, Netherlands [ 106 ] Erasmus Univ, Med Ctr, Family Canc Clin, Dept Med Oncol, NL-3008 AE Rotterdam, Netherlands [ 107 ] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic 3010, Australia [ 108 ] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, 665 Huntington Ave, Boston, MA 02115 USA [ 109 ] NN Petrov Oncol Res Inst, St Petersburg 197758, Russia [ 110 ] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA [ 111 ] Peter MacCallum Canc Ctr, Familial Canc Ctr, Melbourne, Vic 8006, Australia [ 112 ] Univ Melbourne, Dept Oncol, Melbourne, Vic 8006, Australia [ 113 ] State Res Inst, Ctr Innovat Med, LT-08661 Vilnius, Lithuania [ 114 ] Aarhus Univ Hosp, Dept Clin Genet, DK-8200 Aarhus N, Denmark [ 115 ] Canc Prevent Inst Calif, Dept Epidemiol, Fremont, CA 94538 USA [ 116 ] Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England [ 117 ] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA [ 118 ] Univ Helsinki, Dept Obstet & Gynecol, FI-00029 Helsinki, Finland [ 119 ] Univ Helsinki, Cent Hosp, FI-00029 Helsinki, Finland [ 120 ] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England [ 121 ] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada [ 122 ] Evangel Kliniken Bonn gGmbH, Johanniter Krankenhaus, Dept Internal Med, D-53113 Bonn, Germany [ 123 ] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Sch Med, FI-70211 Kuopio, Finland [ 124 ] Hong Kong Hereditary Breast Canc Family Registry, Canc Genet Ctr, Hong Kong Sanat & Hosp, Hong Kong, Hong Kong, Peoples R China [ 125 ] Univ Hong Kong, Dept Surg, Hong Kong, Hong Kong, Peoples R China [ 126 ] VIB, Vesalius Res Ctr, B-3000 Leuven, Belgium [ 127 ] IDIBELL Catalan Inst Oncol, Hereditary Canc Program, Mol Diagnost Unit, Barcelona 08908, Spain [ 128 ] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90032 USA [ 129 ] Univ Canc Ctr, Canc Epidemiol Program, Honolulu, HI 96813 USA [ 130 ] Karolinska Inst, Dept Mol Med & Surg, SE-17177 Stockholm, Sweden [ 131 ] Mayo Clin, Hlth Sci Res, Scotsdale, AZ 85259 USA [ 132 ] Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA [ 133 ] Genome Inst Singapore, Div Human Genet, Singapore 138672, Singapore [ 134 ] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Div Epidemiol,Dept Med, Nashville, TN 37203 USA [ 135 ] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, Nashville, TN 37203 USA [ 136 ] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA [ 137 ] Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA [ 138 ] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Med Genet, I-20133 Milan, Italy [ 139 ] Tech Univ Munich, Dept Obstet & Gynaecol, D-81675 Munich, Germany [ 140 ] Roswell Pk Canc Inst, NRG Oncol Stat & Data Management Ctr, Buffalo, NY 14263 USA [ 141 ] Case Western Reserve Univ, Sch Med, Dept Genom & Genome Sci, Cleveland, OH 44106 USA [ 142 ] Univ Hlth Network, Lab Med Program, Toronto, ON M5B 1W8, Canada [ 143 ] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5B 1W8, Canada [ 144 ] Invitae Corp, San Francisco, CA 94107 USA [ 145 ] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA [ 146 ] Natl Inst Oncol, Dept Mol Genet, H-1122 Budapest, Hungary [ 147 ] Univ Chicago, Med Ctr, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA [ 148 ] Seoul Natl Univ, Coll Med, Dept Prevent Med & Biomed Sci, Seoul 110799, South Korea [ 149 ] Seoul Natl Univ, Canc Res Inst, Seoul 110799, South Korea [ 150 ] Univ Med Ctr, Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol, NL-3508 GA Utrecht, Netherlands [ 151 ] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, MRC PHE Ctr Environm & Hlth, London SW7 2AZ, England [ 152 ] Fdn Ist FIRC Oncol Mol, IFOM, I-20133 Milan, Italy [ 153 ] Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med, Div Human Genet, Columbus, OH 43210 USA [ 154 ] Univ Oulu, NordLab Oulu, Oulu Univ Hosp, Lab Canc Genet & Tumor Biol,Dept Clin Chem, FI-90220 Oulu, Finland [ 155 ] Univ Oulu, NordLab Oulu, Oulu Univ Hosp, Lab Canc Genet & Tumor Biol,Dept Clin Chem, FI-90220 Oulu, Finland [ 156 ] Univ Oulu, NordLab Oulu, Oulu Univ Hosp, Lab Canc Genet & Tumor Biol,Bioctr Oulu, FI-90220 Oulu, Finland [ 157 ] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, I-20133 Milan, Italy [ 158 ] Inst Canc Res, Sect Canc Genet, Sutton SM2 5NG, Surrey, England [ 159 ] Karolinska Univ Hosp, Dept Clin Genet, SE-17176 Stockholm, Sweden [ 160 ] Med Univ Vienna, Ctr Comprehens Canc, Dept Obstet & Gynecol, A-1090 Vienna, Austria [ 161 ] Clalit Natl Israeli Canc Control Ctr, IL-34362 Haifa, Israel [ 162 ] Carmel Hosp, Dept Community Med & Epidemiol, IL-34362 Haifa, Israel [ 163 ] B Rappaport Fac Med, IL-34362 Haifa, Israel [ 164 ] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA [ 165 ] Int Agcy Res Canc, F-69008 Lyon, France [ 166 ] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, NL-1006 BE Amsterdam, Netherlands [ 167 ] Univ Granada, Hosp Univ Granada, Inst Invest Biosanitaria Ibs GRANADA, Escuela Andaluza Salud Publ, E-18014 Granada, Spain [ 168 ] CIBER Epidemiol & Salud Publ CIBERESP, Madrid, Spain [ 169 ] Columbia Univ, Dept Environm Hlth Sci, New York, NY 10032 USA [ 170 ] Kings Coll London, Guys Hosp, Div Canc Studies, Res Oncol, London SE1 9RT, England [ 171 ] Univ Hosp Cologne, Fac Med, Ctr Hereditary Breast & Ovarian Canc, D-50931 Cologne, Germany [ 172 ] Univ Hosp Cologne, Fac Med, CIO, D-50931 Cologne, Germany [ 173 ] Univ Cologne, CMMC, D-50931 Cologne, Germany [ 174 ] John Hunter Hosp, Hunter Area Pathol Serv, Div Genet, Newcastle, NSW 2305, Australia [ 175 ] Univ Kansas, Med Ctr, Dept Hematol & Oncol, Kansas City, KS 66205 USA [ 176 ] Univ Laval, Ctr Hosp Univ Quebec, Res Ctr, Quebec City, PQ G1V 4G2, Canada [ 177 ] Hosp Civils Lyon, Ctr Leon Berard, Unite Mixte Genet Constitut Canc Frequents, F-69373 Lyon, France [ 178 ] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia [ 179 ] Hannover Med Sch, D-30625 Hannover, Germany [ 180 ] Linkoping Univ, Dept Clin & Expt Med, Div Clin Genet, SE-58185 Linkoping, Sweden [ 181 ] Inst Curie, Dept Tumour Biol, F-75248 Paris, France [ 182 ] Univ Paris 05, Sorbonne Paris Cite, F-75248 Paris, France [ 183 ] NHGRI, NIH, Bethesda, MD 20892 USA [ 184 ] Portuguese Oncol Inst, Dept Genet, P-4200072 Oporto, Portugal [ 185 ] Univ Porto, Biomed Sci Inst ICBAS, P-4200072 Oporto, Portugal [ 186 ] Canc Res Initiat Fdn, Sime Darby Med Ctr, Subang Jaya 47500, Malaysia [ 187 ] Univ Malaya, Med Ctr, Canc Res Inst, Fac Med, Kuala Lumpur 50603, Malaysia [ 188 ] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA [ 189 ] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense C, Denmark [ 190 ] Latvian Biomed Res & Study Ctr, LV-1067 Riga, Latvia [ 191 ] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA [ 192 ] Leiden Univ, Med Ctr, Dept Surg Oncol, NL-2333 ZC Leiden, Netherlands [ 193 ] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England [ 194 ] Univ Oxford, Oxford Biomed Res Ctr, Oxford OX3 7BN, England [ 195 ] IDIBELL Catalan Inst Oncol, Hereditary Canc Program, Genet Counseling Unit, Barcelona 08908, Spain [ 196 ] Civ MP Arezzo Hosp, Canc Registry, I-97100 Asp Ragusa, Italy [ 197 ] Civ MP Arezzo Hosp, Histopathol Unit, I-97100 Asp Ragusa, Italy [ 198 ] Beth Israel Deaconess Med Ctr, Dept Med Oncol, Boston, MA 02215 USA [ 199 ] Inst Populat Based Canc Res, Canc Registry Norway, N-0304 Oslo, Norway [ 200 ] Erasmus Univ, Med Ctr, Family Canc Clin, Dept Pathol, NL-3000 CA Rotterdam, Netherlands [ 201 ] Charite, Inst Human Genet, D-13353 Berlin, Germany [ 202 ] NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, Gaithersburg, MD 20877 USA [ 203 ] Univ Hosp Ulm, D-89075 Ulm, Germany [ 204 ] Univ Tromso, Fac Hlth Sci, Dept Community Med, N-9037 Tromso, Norway [ 205 ] Folkhalsan Res Ctr, Genet Epidemiol Grp, Helsinki 2016, Finland [ 206 ] Stanford Univ, Sch Med, Dept Hlth Res Policy Epidemiol, Stanford, CA 94305 USA [ 207 ] Univ Hosp, Dept Gen Med Oncol, Multidisciplinary Breast Ctr, B-3000 Leuven, Belgium [ 208 ] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA [ 209 ] Hosp Univ La Paz, Med Oncol Serv, Madrid 28046, Spain [ 210 ] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA [ 211 ] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld 4029, Australia [ 212 ] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA

Subjects
0301 basic medicine, Oncology, General Physics and Astronomy, Genome-wide association study, Cyclophilins, Breast cancer, 3123 Gynaecology and paediatrics, Risk Factors, Brjóstakrabbamein, Genotype, BRCA2 MUTATION CARRIERS, Medicine and Health Sciences, CONFER SUSCEPTIBILITY, skin and connective tissue diseases, Cancer, GENE-EXPRESSION, Genetics, RISK, tRNA Methyltransferases, Multidisciplinary, Genome, VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, Loci, BRCA1 Protein, Chromosome Mapping, COMMON VARIANTS, IDENTIFY, PANCREATIC-CANCER, 3. Good health, Multidisciplinary Sciences, Biological sciences, Receptors, Estrogen, Chromosomes, Human, Pair 2, Science & Technology - Other Topics, Female, NAF12, medicine.medical_specialty, Heterozygote, Science, 3122 Cancers, Locus (genetics), Breast Neoplasms, Biology, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, Càncer de mama, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, Pancreatic cancer, MD Multidisciplinary, medicine, Genetic predisposition, Journal Article, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, METAANALYSIS, Cancer och onkologi, Science & Technology, VDP::Medical disciplines: 700::Clinical medical disciplines: 750::Oncology: 762, General Chemistry, Arfgengi, medicine.disease, TRNA Methyltransferases, VDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Onkologi: 762, 030104 developmental biology, Cancer and Oncology, Expression quantitative trait loci, Mutation, TELOMERE LENGTH, 3111 Biomedicine, Gene expression, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, Genome-Wide Association Study
Abstract

Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P, B.C.A.C. was funded through a European Community Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175; COGS); Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692); the National Institutes of Health Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), R01 grants (CA128978, CA176785, CA192393), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative); the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Breast Cancer Res. Foundation, and the Ovarian Cancer Research Fund. CIMBA genotyping was supported by National Institutes of Health grant (CA128978); the Department of Defence (W81XWH-10-1-0341); and the Breast Cancer Res. Foundation. CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. This study made use of data generated by the Wellcome Trust Case Control consortium. Functional studies were supported by the Florida Breast Cancer Foundation. A full description of funding and acknowledgments is provided in Supplementary Note 1.

Published
2018
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3. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility

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Tazeen H. Jafar, Lars Lind, Peter Almgren, Wendy Winckler, Eitaro Nakashima, Young Min Cho, Annette Peters, Rona J. Strawbridge, Ananda R. Wickremasinghe, Katharine R. Owen, Lee-Ming Chuang, Tien-Jyun Chang, Graeme I. Bell, James B. Meigs, Bill Musk, Timo A. Lakka, Elin Grundberg, Wei Lu, Sarah Edkins, George Dedoussis, Weiping Jia, Danish Saleheen, Suthesh Sivapalaratnam, Maria Samuel, Tien Yin Wong, Lu Qi, Pierre Fontanillas, Momoko Horikoshi, Jirong Long, Abdul Basit, Anubha Mahajan, Andrew T. Hattersley, Markus M. Nöthen, Denis Rybin, Inger Njølstad, S. Krithika, Miguel Cruz, Delilah Zabaneh, Leena Peltonen, Jasmina Kravic, Sangsoo Kim, David Couper, Lori L. Bonnycastle, Heather M. Stringham, Yi-Cheng Chang, Paul Elliott, Eric J.G. Sijbrands, Nita G. Forouhi, Alena Stančáková, Ghazala Mirza, Robert W. Lawrence, Ruth J. F. Loos, Norman Klopp, Shiro Maeda, Martina Müller-Nurasyid, Jer-Yuarn Wu, Jianjun Liu, Kee Seng Chia, Elodie Eury, Loukianos S. Rallidis, Timothy M. Frayling, Ken Yamamoto, David Altshuler, Gunnar Sigurosson, Harald Grallert, Jackie F. Price, Barbara Thorand, Jouko Saramies, Malene M. Kristensen, Sonali Pechlivanis, Inês Barroso, Jong-Young Lee, Melissa Parkin, Josée Dupuis, Stéphane Lobbens, Jesús Kumate, Elena Tremoli, Sudhir Kowlessur, Xueling Sim, Norihiro Kato, Philippe Froguel, Kathleen Stirrups, Eero Lindholm, Alex S. F. Doney, Andres Metspalu, Yu-Tang Gao, Roman Wennauer, Xiao-Ou Shu, Marilyn C. Cornelis, Veikko Salomaa, Nanette R. Lee, Johanna Kuusisto, Caroline S. Fox, Man Li, James Scott, Wing-Yee So, Andrew R. Wood, Inga Prokopenko, Oddgeir L. Holmen, Tin Aung, Ryoichi Takayanagi, Chen Suo, Hara Kazuo, Carl G. P. Platou, Ann M. Kelly, Teresa Ferreira, Karl-Heinz Jöckel, Wei-Yen Lim, James F. Wilson, Tom Forsén, Qi Sun, Valur Emilsson, Gonçalo R. Abecasis, Fan Zhang, Timo Saaristo, Harry Campbell, Ying Wu, Mark Seielstad, Wei Zheng, Han Chen, Stavroula Kanoni, Yuqian Bao, Jose C. Florez, Wan Ting Tay, Ronald C. WMa, Gerald Steinbach, Min Jin Go, Rong Zhang, Junbin Liang, Vasiliki Lagou, Leif Groop, Emil Rehnberg, Nabi Shah, Weihua Zhang, Yun Li, Bengt Sennblad, Olle Melander, Nancy L. Pedersen, Muhammed Islam, Jaakko Tuomilehto, Young Jin Kim, Richard N. Bergman, Juliana C.N. Chan, Eleftheria Zeggini, Andrew D. Johnson, Kees Hovingh, Joban Sehmi, Rainer Rauramaa, Satu Männistö, Reedik Mägi, Samuel Liju, Mingyu Yang, Ayellet V. Segrè, Noël P. Burtt, Mozhgan Dorkhan, Beverley Balkau, Neelam Hassanali, Hyun Min Kang, Fabrizio Veglia, Eeva Korpi-Hyövälti, Loic Yengo, Elizabeth J. Rossin, Angela Silveira, Maggie C.Y. Ng, Yuan-Tsong Chen, Anders Hamsten, David R. Matthews, Mark J. Caulfield, Emmi Tikkanen, Tanya M. Teslovich, John R. B. Perry, Karen L. Mohlke, Sarah E. Hunt, Soo Heon Kwak, Jorge Escobedo, Christopher J. Groves, Ulf de Faire, Jeremy B M Jowett, Gudmar Thorleifsson, Michael Roden, Evelin Mihailov, Viswanathan Mohan, Craig L. Hanis, Thomas WMühleisen, Congrong Wang, Sonia Shah, Kyle J. Gaulton, Jaspal S. Kooner, Jiro Nakamura, Mustafa Atalay, Linda S. Adair, S Wiltshire, Tõnu Esko, Anna Jonsson, Antigone S. Dimas, Karin Leander, Li Ching Chang, George B. Grant, Bo Isomaa, Anne U. Jackson, Claudia Langenberg, Kristian Hveem, Yoon Shin Cho, Astradur B. Hreidarsson, Xu Wang, Keizo Ohnaka, Alexandra C. Nica, Simon D. Rees, Pau Navarro, Sekar Kathiresan, Rob M. van Dam, Zafar I. Hydrie, Bok Ghee Han, Francis S. Collins, Fuu Jen Tsai, Unnur Thorsteinsdottir, Ross M. Fraser, Caroline Hayward, Cornelia M. van Duijn, Samuli Ripatti, Mieke D. Trip, Hyung Lae Kim, Rafn Benediktsson, Candace Guiducci, Bruna Gigante, Kyong Soo Park, Wen Hong L. Kao, Tom Wilsgaard, Leena Kinnunen, John Danesh, Alan James, Alan R. Shuldiner, Mitsuhiro Yokota, Jen Mai Lee, Kari Stefansson, Erik Ingelsson, Colin N. A. Palmer, David J. Hunter, Paul Zimmet, Manickam Chidambaram, Sirkka Keinänen-Kiukaanniemi, Laura J. Scott, Susanne Moebus, Benjamin F. Voight, Wolfgang Rathmann, Hassan Khan, Thomas Illig, Prasad Katulanda, Christian Gieger, Andrew D. Morris, Yik Ying Teo, Andrew P. Morris, Venkatesan Radha, N. William Rayner, Johan G. Eriksson, Christian Dina, Igor Rudan, Sailaja Vedantam, Cheng Hu, James S. Pankow, Ann-Christine Syvänen, Karl Gertow, Valeriya Lyssenko, Guillaume Charpentier, Albert Hofman, Chiea Chuen Khor, Joseph Trakalo, Peter Kraft, Takashi Kadowaki, Qiuyin Cai, John C. Chambers, André G. Uitterlinden, Simon C. Potter, Nicholas J. Wareham, Soumya Raychaudhuri, Jian'an Luan, Tiinamaija Tuomi, Anthony H. Barnett, Juha Saltevo, Robert A. Scott, Valgerdur Steinthorsdottir, Peng Keat Ng, Mark I. McCarthy, Åsa K. Hedman, Kerrin S. Small, Julia Meyer, Frank B. Hu, Cecilia M. Lindgren, Jennifer E. Below, Nancy J. Cox, Jennie Hui, Andrew Crenshaw, Latonya F. Been, Nam H. Cho, Janani Pinidiyapathirage, A. 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Finland [ 192 ] South Karelia Cent Hosp, Lappeenranta, Finland [ 193 ] UCL, Dept Genet Evolut & Environm, Genet Inst, London, England [ 194 ] Diabet Assoc Pakistan, Karachi, Pakistan [ 195 ] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA [ 196 ] Baltimore Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Baltimore, MD USA [ 197 ] Univ Maryland, Sch Med, Program Personalised & Genom Med, Baltimore, MD 21201 USA [ 198 ] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands [ 199 ] Univ Ulm, Dept Clin Chem, D-89069 Ulm, Germany [ 200 ] Univ Ulm, Cent Lab, D-89069 Ulm, Germany [ 201 ] Uppsala Univ, Dept Med Sci, Uppsala, Sweden [ 202 ] Kyushu Univ, Grad Sch Med Sci, Dept Internal Med & Bioregulatory Sci, Higashi Ku, Fukuoka 812, Japan [ 203 ] Univ Helsinki, Helsinki Univ Hosp, Dept Med, Helsinki, Finland [ 204 ] Hosp Univ LaPaz IdiPAZ, Inst Invest Sanitaria, Madrid, Spain [ 205 ] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria [ 206 ] King Abdulaziz Univ, Diabet Res Grp, Jeddah 21413, Saudi Arabia [ 207 ] IMSS, Ctr Med Nacl Siglo 21, Hosp Especialidades, Unidad Invest Med Bioquim, Mexico City, DF, Mexico [ 208 ] Univ Penn, Perelman Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA [ 209 ] Univ Melbourne, Ctr Eye Res Australia, East Melbourne, Vic, Australia [ 210 ] Kyushu Univ, Med Inst Bioregulat, Res Ctr Genet Informat, Div Genome Anal,Higashi Ku, Fukuoka 812, Japan [ 211 ] Univ Lille 1, Math Lab, CNRS UMR 8524, MODAL Team,INRIA Lille Nord Europe, F-59655 Villeneuve Dascq, France [ 212 ] Aichi Gakuin Univ, Sch Dent, Dept Genome Sci, Nagoya, Aichi 464, Japan [ 213 ] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA [ 214 ] Harvard Univ, Sch Med, Dept Mol Biol, Boston, MA USA [ 215 ] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA [ 216 ] Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA [ 217 ] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA [ 218 ] Hallym Univ, Dept Biomed Sci, Chunchon, Gangwon Do, South Korea [ 219 ] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA [ 220 ] Imperial Coll Healthcare NHS Trust, London, England [ 221 ] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA [ 222 ] Blood Syst Res Inst, San Francisco, CA USA [ 223 ] Natl Univ Singapore, Grad Sch Integrat Sci & Engn, Singapore 117548, Singapore [ 224 ] Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore 117548, Singapore [ 225 ] Natl Univ Singapore, Dept Med, Singapore 117548, Singapore [ 226 ] Duke Natl Univ Singapore, Grad Sch Med, Singapore, Singapore [ 227 ] Univ Liverpool, Dept Biostat, Liverpool L69 3BX, Merseyside, England, Obstetrics & Gynecology, Radiology & Nuclear Medicine, Surgery, Epidemiology, Dermatology, Internal Medicine, Medical Microbiology & Infectious Diseases, Medical Research Council (MRC), National Institute for Health Research, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, and Cardiology

Subjects
CHROMATIN, endocrine system diseases, South Asian Type 2 Diabetes (SAT2D) Consortium, SCALE ASSOCIATION ANALYSIS, Medizin, LOCI, Genome-wide association study, VARIANTS, 0302 clinical medicine, Risk Factors, IMPUTATION, Glucose homeostasis, 11 Medical and Health Sciences, Genetics & Heredity, Genetics, 0303 health sciences, IDENTIFY, Hispanic or Latino, 3. Good health, MAP, POPULATIONS, Medical genetics, Type 2 Diabetes Genetic Exploration by Nex-generation sequencing in muylti-Ethnic Samples (T2D-GENES) Consortium, Hispanic Americans, Life Sciences & Biomedicine, Asian Continental Ancestry Group, medicine.medical_specialty, European Continental Ancestry Group, TRANSETHNIC METAANALYSIS, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, White People, Sykursýki, 03 medical and health sciences, Asian People, SDG 3 - Good Health and Well-being, medicine, Humans, Genetic Predisposition to Disease, Allele, Asian Genetic Epidemiology Network Type 2 Diabetes (AGEN-T2D) Consortium, Alleles, 030304 developmental biology, Genetic association, Science & Technology, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Mexican American Type 2 Diabetes (MAT2D) Consortium, 06 Biological Sciences, Arfgengi, Genetic architecture, INDIVIDUALS, Diabetes Mellitus, Type 2, Case-Control Studies, GLUCOSE-HOMEOSTASIS, ASSOCIATION ANALYSES, Imputation (genetics), Developmental Biology, Genome-Wide Association Study
Abstract

To access publisher's full text version of this article click on the hyperlink at the bottom of the page To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry. Canadian Institutes of Health Research Medical Research Council UK G0601261 Mexico Convocatoria SSA/IMMS/ISSSTE-CONACYT 2012-2 clave 150352 IMSS R-2011-785-018 CONACYT Salud-2007-C01-71068 US National Institutes of Health DK062370 HG000376 DK085584 DK085545 DK073541 DK085501 Wellcome Trust WT098017 WT090532 WT090367 WT098381 WT081682 WT085475 info:eu-repo/grantAgreement/EC/FP7/201413

Published
2014
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4. Global epidemiology of drug resistance after failure of WHO recommended first-line regimens for adult HIV-1 infection: a multicentre retrospective cohort study

Author

Gregson, J, Tang, M, Ndembi, N, Hamers, Rl, Marconi, Vc, Brooks, K, Theys, K, Arruda, M, Garcia, F, Monge, S, Kanki, Pj, Kumarasamy, N, Kerschberger, B, Mor, O, Charpentier, C, Todesco, E, Rokx, C, Gras, L, Halvas, Ek, Sunpath, H, Carlo, Dd, Antinori, A, Andreoni, M, Latini, A, Mussini, C, Aghokeng, A, Sonnerborg, A, Neogi, U, Fessel, Wj, Agolory, S, Yang, C, Blanco, Jl, Juma, Jm, Smit, E, Schmidt, D, Watera, C, Asio, J, Kirungi, W, Tostevin, A, Clumeck, N, Goedhals, D, Bester, Pa, Sabin, C, Mukui, I, Santoro, M, Perno, Cf, Hunt, G, Morris, L, Pillay, D, Schulter, E, Reyes-Teran, G, Romero, K, Avila-Rios, S, Sirivichayakul, S, Ruxrungtham, K, Mekprasan, S, Dunn, D, Kaleebu, P, Raizes, E, Kantor, R, Gupta, Rk, Rhee, S, Shafer, Rw, de Wit, Tfr, Diero, L, Camacho, R, Gunthard, Hf, Hoffmann, Cj, Di Carlo, D, El-Hay, T, van Vuuren, C, de Oliveira, T, Murakami-Ogasawara, A, [Pillay, Deenan] UCL, Dept Infect, London WC1E 6BT, England, [Gupta, Ravindra K.] UCL, Dept Infect, London WC1E 6BT, England, [Tang, Michele] Stanford Univ, Dept Med, Stanford, CA 94305 USA, [Rhee, Soo-Yon] Stanford Univ, Dept Med, Stanford, CA 94305 USA, [Shafer, Robert W.] Stanford Univ, Dept Med, Stanford, CA 94305 USA, [Gregson, John] London Sch Hyg & Trop Med, Dept Stat, London, England, [Ndembi, Nicaise] Inst Human Virol Nigeria, Abuja, Federal Capital, Nigeria, [Hamers, Raph L.] Univ Amsterdam, Acad Med Ctr, Amsterdam Inst Global Hlth & Dev, Dept Global Hlth, NL-1012 WX Amsterdam, Netherlands, [de Wit, Tobias F. Rinke] Univ Amsterdam, Acad Med Ctr, Amsterdam Inst Global Hlth & Dev, Dept Global Hlth, NL-1012 WX Amsterdam, Netherlands, [Hamers, Raph L.] Univ Amsterdam, Acad Med Ctr, Dept Internal Med, NL-1012 WX Amsterdam, Netherlands, [de Wit, Tobias F. Rinke] Univ Amsterdam, Acad Med Ctr, Dept Internal Med, NL-1012 WX Amsterdam, Netherlands, [Marconi, Vincent C.] Emory Univ, Rollins Sch Publ Hlth, Dept Global Hlth, Atlanta, GA 30322 USA, [Marconi, Vincent C.] Emory Univ, Sch Med, Div Infect Dis, Atlanta, GA USA, [Diero, Lameck] Moi Univ, Eldoret, Kenya, [Diero, Lameck] Acad Model Providing Access Healthcare, Eldoret, Kenya, [Brooks, Katherine] Brown Univ, Alpert Med Sch, Div Infect Dis, Providence, RI 02912 USA, [Theys, Kristof] KU Leuven Univ Leuven, Rega Inst Med Res, Dept Microbiol & Immunol, B-3000 Leuven, Belgium, [Camacho, Ricardo] KU Leuven Univ Leuven, Rega Inst Med Res, Dept Microbiol & Immunol, B-3000 Leuven, Belgium, [Kantor, Rami] KU Leuven Univ Leuven, Rega Inst Med Res, Dept Microbiol & Immunol, B-3000 Leuven, Belgium, [Arruda, Monica] Univ Fed Rio de Janeiro, Inst Biol, LVM, BR-21941 Rio De Janeiro, Brazil, [Garcia, Frederico] Complejo Hosp Univ Granada, Granada, Spain, Univ Alcala de Henares, E-28871 Alcala De Henares, Spain, [Monge, Susana] CIBERESP, Madrid, Spain, [Gunthard, Huldrych F.] Univ Zurich, Div Infect Dis & Hosp Epidemiol, Zurich, Switzerland, [Gunthard, Huldrych F.] Univ Zurich, Inst Med Virol, Zurich, Switzerland, [Hoffmann, Christopher J.] Johns Hopkins Univ, Baltimore, MD USA, [Hoffmann, Christopher J.] Aurum Inst, Johannesburg, South Africa, [Kanki, Phyllis J.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA, [Kumarasamy, Nagalingeshwaran] VHS, YRGCARE Med Ctr, Chennai, Tamil Nadu, India, [Kerschberger, Bernard] Med Sans Frontieres Operat Ctr Geneva, Mbabane, Eswatini, [Mor, Orna] Israel Minist Hlth, Publ Hlth Serv, Cent Virol Lab, Jerusalem, Israel, [Charpentier, Charlotte] Univ Paris Diderot, Sorbonne Paris Cite, IAME, UMR 1137, Paris, France, [Charpentier, Charlotte] INSERM, IAME, UMR 1137, Paris, France, [Charpentier, Charlotte] Hop Bichat Claude Bernard, AP HP, Virol Lab, F-75018 Paris, France, [Todesco, Eva] Hop La Pitie Salpetriere, Lab Virol, Paris, France, [Rokx, Casper] Erasmus Univ, Med Ctr, Dept Internal Med Infect Dis, Rotterdam, Netherlands, [Gras, Luuk] Stichting HIV Monitoring, Amsterdam, Netherlands, [Halvas, Elias K.] Univ Pittsburgh, Pittsburgh, PA USA, [Sunpath, Henry] Ethekwini Dist Hlth Off, Kwa Zulu, South Africa, [Di Carlo, Domenico] Univ Roma Tor Vergata, Dept Expt Med & Surg, Rome, Italy, [Santoro, Maria M.] Univ Roma Tor Vergata, Dept Expt Med & Surg, Rome, Italy, [Antinori, Antonio] INMI L Spallanzani, Infect Dis Unit, Rome, Italy, [Andreoni, Massimo] Univ Hosp Tor Vergata, Clin Infect Dis, Rome, Italy, [Latini, Alessandra] San Gallicano Dermatol Inst, HIV AIDS Unit, Rome, Italy, [Mussini, Cristina] Azienda Osped Univ Policlin, Clin Infect Dis, Modena, Italy, [Aghokeng, Avelin] Virol Lab CREMER IMPM, Yaounde, Cameroon, [Sonnerborg, Anders] Karolinska Inst, Div Clin Microbiol, Stockholm, Sweden, [Neogi, Ujjwal] Karolinska Inst, Div Clin Microbiol, Stockholm, Sweden, [Sonnerborg, Anders] Karolinska Inst, Infect Dis Unit, Stockholm, Sweden, [Neogi, Ujjwal] Karolinska Inst, Infect Dis Unit, Stockholm, Sweden, [Sonnerborg, Anders] Karolinska Univ Hosp, Stockholm, Sweden, [Neogi, Ujjwal] Karolinska Univ Hosp, Stockholm, Sweden, [Fessel, William J.] Kaiser Permanente Med Care Program Northern Calif, San Francisco, CA USA, [Agolory, Simon] Ctr Dis Control & Prevent, Div Global HIV AIDS, Ctr Global Hlth, Atlanta, GA USA, [Raizes, Elliot] Ctr Dis Control & Prevent, Div Global HIV AIDS, Ctr Global Hlth, Atlanta, GA USA, [Yang, Chunfu] Ctr Dis Control & Prevent, Int Lab Branch, Div Global HIV AIDS, Ctr Global Hlth, Atlanta, GA USA, [Blanco, Jose L.] Univ Barcelona, Inst Invest Biomed August Pi i Sunyer, Clin Univ, Barcelona, Spain, [Juma, James M.] Minist Hlth & Social Welf, Dar Es Salaam, Tanzania, [Smit, Erasmus] Publ Hlth England, Publ Hlth Lab, Birmingham, W Midlands, England, [Schmidt, Daniel] Robert Koch Inst, Dept Infect Dis Epidemiol HIV AIDS STI & Blood Bo, Berlin, Germany, [Watera, Christine] Uganda Res Unit AIDS, Entebbe, Uganda, [Asio, Juliet] Uganda Res Unit AIDS, Entebbe, Uganda, [Kaleebu, Pontiano] Uganda Res Unit AIDS, Entebbe, Uganda, [Tostevin, Anna] Minist Hlth, Kampala, Uganda, [Tostevin, Anna] UCL, MRC Clin Trials Unit, London, England, [Dunn, David] UCL, MRC Clin Trials Unit, London, England, [El-Hay, Tal] IBM Haifa Res Lab, Haifa, Israel, [Clumeck, Nathan] Univ Libre Bruxelles, St Pierre Univ Hosp, Brussels, Belgium, [Goedhals, Dominique] Univ Orange Free State, Dept Med Microbiol & Virol, Natl Hlth Lab Serv, Bloemfontein, South Africa, [van Vuuren, Cloete] Univ Orange Free State, Dept Med Microbiol & Virol, Natl Hlth Lab Serv, Bloemfontein, South Africa, [Sabin, Caroline] UCL, Infect & Populat Hlth, London, England, [Mukui, Irene] Minist Hlth, Natl AIDS & STI Control Programme, Nairobi, Kenya, [Perno, Carlo F.] INMI L Spallanzani, Antiretroviral Drugs Monitoring Unit, Rome, Italy, [Hunt, Gillian] Natl Inst Communicable Dis, Johannesburg, South Africa, [Morris, Lynn] Natl Inst Communicable Dis, Johannesburg, South Africa, [de Oliveira, Tulio] Wellcome Trust Africa Ctr Hlth & Populat Studies, Durban, South Africa, [Pillay, Deenan] Wellcome Trust Africa Ctr Hlth & Populat Studies, Durban, South Africa, [de Oliveira, Tulio] Univ KwaZulu Natal, Coll Hlth Sci, Durban, South Africa, [Schulter, Eugene] Univ Cologne, Inst Virol, D-50931 Cologne, Germany, [Murakami-Ogasawara, Akio] Natl Inst Resp Dis, Ctr Res Infect Dis, Mexico City, DF, Mexico, [Sirivichayakul, Sunee] Chulalongkorn Univ, Dept Med, Bangkok, Thailand, [Ruxrungtham, Kiat] Chulalongkorn Univ, Dept Med, Bangkok, Thailand, [Mekprasan, Suwanna] Chulalongkorn Univ, Dept Med, Bangkok, Thailand, [Kaleebu, Pontiano] MRC UVRI Uganda Res Unit AIDS, Entebbe, Uganda, Wellcome Trust, MRC, NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES, and Medical Research Council

Subjects
Cyclopropanes, Anti-HIV Agents, K65r, Drug Resistance, Antiretroviral Therapy, HIV Infections, Global Health, Settore MED/07, Virological failure, Tenofovir disoproxil fumarate, Antiretroviral Therapy, Highly Active, Drug Resistance, Viral, Humans, Emtricitabine, Transmission, Highly Active, Viral, Tenofovir, Africa South of the Sahara, Benzoxazines, HIV-1, Lamivudine, Pre-Exposure Prophylaxis, Retrospective Studies, Reverse Transcriptase Inhibitors, Viral Load, Hiv-1-infected patients, virus diseases, Articles, Antiretroviral therapy, Naive patients, Alkynes, Efavirenz
Abstract

Summary Background Antiretroviral therapy (ART) is crucial for controlling HIV-1 infection through wide-scale treatment as prevention and pre-exposure prophylaxis (PrEP). Potent tenofovir disoproxil fumarate-containing regimens are increasingly used to treat and prevent HIV, although few data exist for frequency and risk factors of acquired drug resistance in regions hardest hit by the HIV pandemic. We aimed to do a global assessment of drug resistance after virological failure with first-line tenofovir-containing ART. Methods The TenoRes collaboration comprises adult HIV treatment cohorts and clinical trials of HIV drug resistance testing in Europe, Latin and North America, sub-Saharan Africa, and Asia. We extracted and harmonised data for patients undergoing genotypic resistance testing after virological failure with a first-line regimen containing tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleotide reverse-transcriptase inhibitor (NNRTI; efavirenz or nevirapine). We used an individual participant-level meta-analysis and multiple logistic regression to identify covariates associated with drug resistance. Our primary outcome was tenofovir resistance, defined as presence of K65R/N or K70E/G/Q mutations in the reverse transcriptase (RT) gene. Findings We included 1926 patients from 36 countries with treatment failure between 1998 and 2015. Prevalence of tenofovir resistance was highest in sub-Saharan Africa (370/654 [57%]). Pre-ART CD4 cell count was the covariate most strongly associated with the development of tenofovir resistance (odds ratio [OR] 1·50, 95% CI 1·27–1·77 for CD4 cell count

Published
2016

5. Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170

Author

Jirong Long, Simon S. Cross, Marc Tischkowitz, Beth Y. Karlan, Trinidad Caldés, Fergus J. Couch, Charlotte Sagne, Ute Hamann, Olga M. Sinilnikova, Maria Kabisch, Richard C Sallari, Gad Rennert, Daniel Barrowdale, Elinor J. Sawyer, Anthony J. Swerdlow, Jenny Lester, Åke Borg, Anders Bojesen, Rosa B. Barkardottir, Simon A. Gayther, Heli Nevanlinna, Judy Garber, Norbert Arnold, Vilde Drageset Haakensen, Vessela N. Kristensen, Christopher G. Scott, Daehee Kang, Gillian Mitchell, Eitan Friedman, Laura Ottini, Diether Lambrechts, Manjeet K. Bolla, Robert L. Nussbaum, Tomasz Huzarski, Dieter Niederacher, Angela Cox, Rachel Laframboise, Maartje J. Hooning, Volker Arndt, Penny Soucy, Marjanka K. Schmidt, William Blot, Soo Hwang Teo, Anne Lise Børresen-Dale, Maria A. Caligo, Ana Osorio, Orland Diez, Gertraud Maskarinec, Johanna Rantala, Kelly-Anne Phillips, Pascal Guénel, Hidemi Ito, Miquel Angel Pujana, Anna H. Wu, Christy G. Woolcott, Maya Ghoussaini, Hatef Darabi, Sander Canisius, Kay-Tee Khaw, Irene Konstantopoulou, Carl Blomqvist, Christine Rappaport, Joan Brunet, Hermann Brenner, Sylvie Mazoyer, Irene L. Andrulis, Nicholas A Sinnott-Armstrong, Javier Benitez, Claudine Isaacs, Mahdi Moradi Marjaneh, Joseph Vijai, Jennifer Stone, Qin Wang, Caroline Seynaeve, Patricia A. Ganz, Sara Margolin, Paolo Radice, Janet E. Olson, Soo-Chin Lee, Mark H. Greene, Laura Papi, Carmel Apicella, Ava Kwong, Mitul Shah, Matthias W. Beckmann, Yael Laitman, Hoda Anton-Culver, Ans M.W. van den Ouweland, Sue K. Park, Annegien Broeks, Georgia Chenevix-Trench, Jonathan Beesley, Nadja Bogdanova-Markov, Paolo Peterlongo, Paraskevi Apostolou, Bernardo Bonanni, Frederik Marmé, Veli-Matti Kosma, Alfons Meindl, Brian E. Henderson, Rulla M. Tamimi, Siranoush Manoukian, Bent Ejlertsen, Miroslav Kapuscinski, Juliet D. French, Mark E. Sherman, Ji Yeob Choi, Graham G. Giles, Stacey L. Edwards, Evgeny N. Imyanitov, Kamila Czene, Thomas Hansen, Nick Orr, Susanne Kaufmann, Lenka Foretova, Celine M. Vachon, Edith Olah, Anja Rudolph, Arto Mannermaa, Phuong L. Mai, Isabel dos-Santos-Silva, Haran Sivakumaran, Francesca Damiola, Christian F. Singer, Muhammad Usman Rashid, Ed Dicks, Mikael Hartman, Antonis C. Antoniou, Dominique Stoppa-Lyonnet, Douglas F. Easton, Alison M. Dunning, John L. Hopper, Nadine Tung, Annika Lindblom, Kristiina Aittomäki, Kenneth Muir, Sue Healey, Cheng Har Yip, Mads Thomassen, Melissa C. Southey, Ramunas Janavicius, Cecilia M. Dorfling, Christine B. Ambrosone, Siddhartha Kar, Mary B. Daly, Artitaya Lophatananon, Rachel Rando, Banu Arun, Christopher A. Haiman, Catherine M. Phelan, Margaret Hills, Manuel R. Teixeira, Diana Torres, Hans Wildiers, Andrew K. Godwin, Keith Humphreys, Katri Pylkäs, Monika Jarosz, Susan L. Neuhausen, Montserrat Garcia-Closas, Robert Winqvist, Joe Dennis, Sook-Yee Yoon, Wei Zheng, Mitch Dowsett, Gord Glendon, Natasha Bogdanova, Suleeporn Sangrajrang, Steve Ellis, Paul Brennan, Lee Eunjung, Keitaro Matsuo, Jacek Gronwald, David E. Goldgar, Debra Frost, Chiu-Chen Tseng, Henrik Flyger, Kristine M. Hillman, Susan M. Domchek, Elena Lopez-Knowles, Bernard Peissel, Anna von Wachenfeldt, Karoline Kuchenbaecker, Anna Jakubowska, Paul D.P. Pharoah, Jose Ignacio Arias Perez, Kim De Leeneer, Roger L. Milne, Peter A. Fasching, Louise Izatt, Saundra S. Buys, Lesley McGuffog, Elizabeth J. van Rensburg, Pei-Ei Wu, Peter Devilee, Åslaug Helland, Qiuyin Cai, Peter J. Hulick, Miguel de la Hoya, Esther M. John, Kerstin Rhiem, Jan Lubinski, Karen A. Pooley, Marion Piedmonte, Catherine S. Healey, Mark S. Goldberg, Xiao-Ou Shu, Antoinette Hollestelle, Mary Beth Terry, Jenny Chang-Claude, Silje Nord, Chen-Yang Shen, Hiltrud Brauch, Kathleen Claes, Jason Sang Hun Lee, Sofia Khan, Katherine L. Nathanson, Hans Ehrencrona, Olufunmilayo I. Olopade, Stig E. Bojesen, Matti A. Rookus, Andrew Lee, Rita K. Schmutzler, Julian Peto, Jeffrey N. Weitzel, Barbara Burwinkel, Arjen R. Mensenkamp, Jacques Simard, Yu-Tang Gao, Robert Luben, S. Drury, Thilo Dörk, Laima Tihomirova, Per Hall, Barbara Perkins, Simona Agata, Jonine D. Figueroa, Julia A. Knight, Kenneth Offit, Kyriaki Michailidou, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Anna Marie Mulligan, Noralane M. Lindor, Deborah J. Thompson, Marco Montagna, Clinical Genetics, Medical Oncology, Obstetrics & Gynecology, Dunning, Alison [0000-0001-6651-7166], Thompson, Deborah [0000-0003-1465-5799], Pooley, Karen [0000-0002-1274-9460], Dicks, Ed [0000-0002-0617-0401], Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Ghoussaini, Maya [0000-0002-2415-2143], Lee, Andrew [0000-0003-0677-0252], Tischkowitz, Marc [0000-0002-7880-0628], Luben, Robert [0000-0002-5088-6343], Khaw, Kay-Tee [0000-0002-8802-2903], Pharoah, Paul [0000-0001-8494-732X], Antoniou, Antonis [0000-0001-9223-3116], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Targeted Gynaecologic Oncology (TARGON), Damage and Repair in Cancer Development and Cancer Treatment (DARE), and [ 1 ] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England [ 2 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England [ 3 ] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld, Australia [ 4 ] Breakthrough Breast Canc Res Ctr, Breast Canc Res, London, England [ 5 ] Royal Marsden Hosp, Acad Biochem, London SW3 6JJ, England [ 6 ] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA [ 7 ] MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA [ 8 ] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands [ 9 ] Univ Melbourne, Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic, Australia [ 10 ] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia [ 11 ] Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry CV4 7AL, W Midlands, England [ 12 ] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England [ 13 ] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Gynecol & Obstet, Comprehens Canc Ctr Erlangen Nuremberg Metropolit, D-91054 Erlangen, Germany [ 14 ] Univ Calif Los Angeles, David Geffen Sch Med, Div Hematol & Oncol, Dept Med, Los Angeles, CA 90095 USA [ 15 ] London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London WC1, England [ 16 ] Kings Coll London, Guys Hosp, Div Canc Studies, Res Oncol, London, England [ 17 ] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England [ 18 ] Univ Oxford, Oxford Biomed Res Ctr, Oxford, England [ 19 ] German Canc Res Ctr, Div Mol Genet Epidemiol, Heidelberg, Germany [ 20 ] German Canc Res Ctr, Mol Epidemiol Grp, Heidelberg, Germany [ 21 ] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany [ 22 ] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany [ 23 ] INSERM, Ctr Res Epidemiol & Populat Hlth, Environm Epidemiol Canc, Villejuif, France [ 24 ] Univ Paris Sud, Villejuif, France [ 25 ] Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, Herlev, Denmark [ 26 ] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev, Denmark [ 27 ] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark [ 28 ] Copenhagen Univ Hosp, Herlev Hosp, Dept Breast Surg, Herlev, Denmark [ 29 ] Spanish Natl Canc Ctr CNIO, Human Canc Genet Program, Madrid, Spain [ 30 ] Hosp Monte Naranco, Serv Cirugia Gen & Especialidades, Oviedo, Spain [ 31 ] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA [ 32 ] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA [ 33 ] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany [ 34 ] German Canc Res Ctr, German Canc Consortium, Heidelberg, Germany [ 35 ] Tech Univ Munich, Dept Obstet & Gynaecol, D-80290 Munich, Germany [ 36 ] Univ Hosp Cologne, Dept Obstet & Gynaecol, Div Mol Gynecooncol, Cologne, Germany [ 37 ] Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Cologne, Germany [ 38 ] Univ Hosp, Ctr Integrated Oncol, Cologne, Germany [ 39 ] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Auerbachstr 112, Stuttgart, Germany [ 40 ] Univ Tubingen, Tubingen, Germany [ 41 ] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany [ 42 ] Helsinki Univ Cent Hosp, Dept Clin Genet, Helsinki, Finland [ 43 ] Univ Helsinki, Helsinki Univ Cent Hosp, Dept Oncol, Helsinki, Finland [ 44 ] Aichi Canc Ctr Res Inst, Div Epidemiol & Prevent, Aichi, Japan [ 45 ] Aichi Canc Ctr Res Inst, Div Mol Med, Nagoya, Aichi, Japan [ 46 ] Hannover Med Sch, Radiat Oncol Res Unit, Hannover, Germany [ 47 ] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany [ 48 ] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden [ 49 ] Karolinska Univ Hosp, Dept Oncol Pathol, Stockholm, Sweden [ 50 ] Kuopio Univ Hosp, Ctr Canc, SF-70210 Kuopio, Finland [ 51 ] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Kuopio, Finland [ 52 ] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, SF-70210 Kuopio, Finland [ 53 ] Vesalius Res Ctr, Leuven, Belgium [ 54 ] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium [ 55 ] Univ Hosp Leuven, Dept Gen Med Oncol, Multidisciplinary Breast Ctr, Leuven, Belgium [ 56 ] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany [ 57 ] Univ Med Ctr Hamburg 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Subjects
0301 basic medicine, Genes, BRCA2, Estrogen receptor, MODIFIERS, Gene Expression, Genome-wide association study, Cell Cycle Proteins, DISEASE, Breast cancer, Risk Factors, Brjóstakrabbamein, BRCA2 MUTATION CARRIERS, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], SUSCEPTIBILITY LOCUS, MAMMOGRAPHIC DENSITY, Regulation of gene expression, Genetics, Research Support, Non-U.S. Gov't, Estrogen Receptor alpha/genetics, Phenotype, 3. Good health, Gene Expression Regulation, Neoplastic, Medical genetics, Chromosomes, Human, Pair 6, Female, BONE-MINERAL DENSITY, NAF12, Protein Binding, EXPRESSION, medicine.medical_specialty, Locus (genetics), Breast Neoplasms, Estrògens, Biology, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, Article, Càncer de mama, 03 medical and health sciences, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, REVEALS, medicine, Journal Article, cancer, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, METAANALYSIS, breast, Genetic Association Studies, Base Sequence, Estrogen Receptor alpha, Genetic Variation, Arfgengi, medicine.disease, Estrogen, 030104 developmental biology, breast cancer, BRCA1, BRCA2, Carrier Proteins, Estrogen receptor alpha, Research Support, U.S. Gov't, Non-P.H.S, Meta-Analysis
Abstract

To access publisher's full text version of this article click on the hyperlink at the bottom of the page We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression. National Institute for Health Research (NIHR) info:eu-repo/grantAgreement/EC/FP7/223175 Cancer Research UK C1287/A10118 C1287/A10710 C12292/A11174 C1281/A12014 C5047/A8384 C5047/A15007 C5047/A10692 C8197/A16565 US National Institutes of Health (NIH) CA128978 CA192393 CA116167 CA176785 US National Institutes of Health (NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer) CA116201 Post-Cancer GWAS initiative 1U19 CA148537 1U19 CA148065 1U19 CA148112 Post-Cancer GWAS initiative (GAME-ON initiative) US Department of Defense W81XWH-10-1-0341 Canadian Institutes of Health Research (CIHR) Komen Foundation for the Cure Breast Cancer Research Foundation Ovarian Cancer Research Fund

Published
2016
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6. BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Author

Meeks, H.D., Song, H.L., Michailidou, K., Bolla, M.K., Dennis, J., Wang, Q., Barrowdale, D., Frost, D., McGuffog, L., Ellis, S., Feng, B.J., Buys, S.S., Hopper, J.L., Southey, M.C., Tesoriero, A., James, P.A., Bruinsma, F., Campbell, I.G., Broeks, A., Schmidt, M.K., Hogervorst, F.B.L., Beckman, M.W., Fasching, P.A., Fletcher, O., Johnson, N., Sawyer, E.J., Riboli, E., Banerjee, S., Menon, U., Tomlinson, I., Burwinkel, B., Hamann, U., Marme, F., Rudolph, A., Janavicius, R., Tihomirova, L., Tung, N., Garber, J., Cramer, D., Terry, K.L., Poole, E.M., Tworoger, S.S., Dorfling, C.M., Rensburg, E.J. van, Godwin, A.K., Guenel, P., Truong, T., Stoppa-Lyonnet, D., Damiola, F., Mazoyer, S., Sinilnikova, O.M., Isaacs, C., Maugard, C., Bojesen, S.E., Flyger, H., Gerdes, A.M., Hansen, T.V.O., Jensen, A., Kjaer, S.K., Hogdall, C., Hogdall, E., Pedersen, I.S., Thomassen, M., Benitez, J., Gonzalez-Neira, A., Osorio, A., Hoya, M. de la, Segura, P.P., Diez, O., Lazaro, C., Brunet, J., Anton-Culver, H., Eunjung, L., John, E.M., Neuhausen, S.L., Ding, Y.C., Castillo, D., Weitzel, J.N., Ganz, P.A., Nussbaum, R.L., Chan, S.B., Karlan, B.Y., Lester, J., Wu, A., Gayther, S., Ramus, S.J., Sieh, W., Whittermore, A.S., Monteiro, A.N.A., Phelan, C.M., Terry, M.B., Piedmonte, M., Offit, K., Robson, M., Levine, D., Moysich, K.B., Cannioto, R., Olson, S.H., Daly, M.B., Nathanson, K.L., Domchek, S.M., Lu, K.H., Liang, D., Hildebrant, M.A.T., Ness, R., Modugno, F., Pearce, L., Goodman, M.T., Thompson, P.J., Brenner, H., Butterbach, K., Meindl, A., Hahnen, E., Wappenschmidt, B., Brauch, H., Bruning, T., Blomqvist, C., Khan, S., Nevanlinna, H., Pelttari, L.M., Aittomaki, K., Butzow, R., Bogdanova, N.V., Dork, T., Lindblom, A., Margolin, S., Rantala, J., Kosma, V.M., Mannermaa, A., Lambrechts, D., Neven, P., Claes, K.B.M., Maerken, T. van, Chang-Claude, J., Flesch-Janys, D., Heitz, F., Varon-Mateeva, R., Peterlongo, P., Radice, P., Viel, A., Barile, M., Peissel, B., Manoukian, S., Montagna, M., Oliani, C., Peixoto, A., Teixeira, M.R., Collavoli, A., Hallberg, E., Olson, J.E., Goode, E.L., Hart, S.N., Shimelis, H., Cunningham, J.M., Giles, G.G., Milne, R.L., Healey, S., Tucker, K., Haiman, C.A., Henderson, B.E., Goldberg, M.S., Tischkowitz, M., Simard, J., Soucy, P., Eccles, D.M., N. le, Borresen-Dale, A.L., Kristensen, V., Salvesen, H.B., Bjorge, L., Bandera, E.V., Risch, H., Zheng, W., Beeghly-Fadiel, A., Cai, H., Pylkas, K., Tollenaar, R.A.E.M., Ouweland, A.M.W. van der, Andrulis, I.L., Knight, J.A., Narod, S., Devilee, P., Winqvist, R., Figueroa, J., Greene, M.H., Mai, P.L., Loud, J.T., Garcia-Closas, M., Schoemaker, M.J., Czene, K., Darabi, H., McNeish, I., Siddiquil, N., Glasspool, R., Kwong, A., Park, S.K., Teo, S.H., Yoon, S.Y., Matsuo, K., Hosono, S., Woo, Y.L., Gao, Y.T., Foretova, L., Singer, C.F., Rappaport-Feurhauser, C., Friedman, E., Laitman, Y., Rennert, G., Imyanitov, E.N., Hulick, P.J., Olopade, O.I., Senter, L., Olah, E., Doherty, J.A., Schildkraut, J., Koppert, L.B., Kiemeney, L.A., Massuger, L.F.A.G., Cook, L.S., Pejovic, T., Li, J.M., Borg, A., Ofverholm, A., Rossing, M.A., Wentzensen, N., Henriksson, K., Cox, A., Cross, S.S., Pasini, B.J., Shah, M., Kabisch, M., Torres, D., Jakubowska, A., Lubinski, J., Gronwald, J., Agnarsson, B.A., Kupryjanczyk, J., Moes-Sosnowska, J., Fostira, F., Konstantopoulou, I., Slager, S., Jones, M., Antoniou, A.C., Berchuck, A., Swerdlow, A., Chenevix-Trench, G., Dunning, A.M., Pharoah, P.D.P., Hall, P., Easton, D.F., Couch, F.J., Spurdle, A.B., Goldgar, D.E., EMBRACE, kConFab Investigators, Australia Ovarian Canc Study Grp, HEBON, GEMO Study Collaborators, OCGN, PRostate Canc Assoc Grp, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Clinical Genetics, Obstetrics & Gynecology, Surgery, and [ 1 ] Univ Utah, Huntsman Canc Inst, Canc Control & Populat Sci, Salt Lake City, UT USA [ 2 ] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England [ 3 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England [ 4 ] Univ Utah, Sch Med, Huntsman Canc Inst, Dept Dermatol, 2000 Circle Hope Dr, Salt Lake City, UT 84112 USA [ 5 ] Univ Utah, Sch Med, Dept Med, Huntsman Canc Inst, Salt Lake City, UT USA [ 6 ] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia [ 7 ] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia [ 8 ] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Parkville, Vic 3052, Australia [ 9 ] KConFab Kathleen Cuningham Consortium Res Familia, Peter MacCallum Canc Ctr, Melbourne, Vic, Australia [ 10 ] Peter MacCallum Canc Ctr, Familial Canc Ctr, Melbourne, Vic, Australia [ 11 ] Univ Melbourne, Dept Oncol, Melbourne, Vic, Australia [ 12 ] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia [ 13 ] Univ Melbourne, Peter MacCallum Canc Ctr, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3052, Australia [ 14 ] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld, Australia [ 15 ] Peter MacCallum Canc Inst, East Melbourne, Vic, Australia [ 16 ] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands [ 17 ] Netherlands Canc Inst, Family Canc Clin, Amsterdam, Netherlands [ 18 ] Netherlands Canc Inst, Hereditary Breast & Ovarian Canc Res Grp Netherla, Coordinating Ctr, Amsterdam, Netherlands [ 19 ] Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen EMN, Univ Hosp Erlangen, Dept Gynaecol & Ostetr, D-91054 Erlangen, Germany [ 20 ] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA [ 21 ] Inst Canc Res, Div Breast Canc Res, London SW3 6JB, England [ 22 ] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England [ 23 ] Guys Hosp, Kings Coll London, Div Canc Studies, Res Oncol, London SE1 9RT, England [ 24 ] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, 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Ctr Familial Breast & Ovarian Canc, Cologne, Germany [ 112 ] Univ Hosp Cologne, Dept Obstet & Gynaecol, Cologne, Germany [ 113 ] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Auerbachstr 112, Stuttgart, Germany [ 114 ] Univ Tubingen, Tubingen, Germany [ 115 ] Ruhr Univ Bochum IPA, German Social Accid Insurance & Inst, Inst Prevent & Occupat Med, Bochum, Germany [ 116 ] Univ Helsinki, Dept Oncol, Helsinki, Finland [ 117 ] Helsinki Univ Hosp, Helsinki, Finland [ 118 ] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland [ 119 ] Univ Helsinki, Dept Clin Genet, Helsinki, Finland [ 120 ] Univ Helsinki, Dept Pathol, Helsinki, Finland [ 121 ] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany [ 122 ] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden [ 123 ] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden [ 124 ] Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden [ 125 ] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Sch Med, Kuopio, Finland [ 126 ] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, SF-70210 Kuopio, Finland [ 127 ] Kuopio Univ Hosp, Ctr Canc, SF-70210 Kuopio, Finland [ 128 ] VIB, VRC, Leuven, Belgium [ 129 ] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium [ 130 ] Univ Hosp Leuven, Dept Oncol, Multidisciplinary Breast Ctr, Leuven, Belgium [ 131 ] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium [ 132 ] Univ Med Ctr Hamburg Eppendorf, Inst Med Biometr & Epidemiol, Hamburg, Germany [ 133 ] Univ Med Ctr Hamburg Eppendorf, Clin Canc Registry, Dept Canc Epidemiol, Hamburg, Germany [ 134 ] Kliniken Essen Mitte Evang Huyssens Stiftung Knap, Dept Gynecol & Gynecol Oncol, Essen, Germany [ 135 ] Dr Horst Schmidt Kliniken Wiesbaden, Dept Gynecol & Gynecol Oncol, Wiesbaden, Germany [ 136 ] Charite, Campus Virchov Klinikum, Inst Human Genet, Berlin, Germany [ 137 ] Fdn Ist FIRC Oncol Mol, IFOM, Milan, Italy [ 138 ] Fdn IRCCS Ist Nazl Tumori, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, Milan, Italy [ 139 ] Aviano Natl Canc Inst, CRO, Div Expt Oncol, Aviano, Italy [ 140 ] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy [ 141 ] Fdn IRCCS Ist Nazl Tumori, Dept Prevent & Predict Med, Unit Med Genet, Milan, Italy [ 142 ] Veneto Inst Oncol IOV IRCCS, Immunol & Mol Oncol Unit, Padua, Italy [ 143 ] ULSS5 Ovest Vicentino, UOC Oncol, Veneto, Italy [ 144 ] Portugese Oncol Inst, Dept Genet, Oporto, Portugal [ 145 ] Univ Porto, Biomed Sci Inst ICBAS, Rua Campo Alegre 823, P-4100 Oporto, Portugal [ 146 ] Univ Pisa, Dept Lab Med, Sect Genet Oncol, Pisa, Italy [ 147 ] Univ Hosp Pisa, Pisa, Italy [ 148 ] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA [ 149 ] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA [ 150 ] Prince Wales Hosp, Sydney, NSW, Australia [ 151 ] McGill Univ, Royal Victoria Hosp, Div Clin Epidemiol, Montreal, PQ H3A 1A1, Canada [ 152 ] McGill Univ, Dept Med, Montreal, PQ, Canada [ 153 ] McGill Univ, Dept Human Genet, Program Canc Genet, Montreal, PQ, Canada [ 154 ] McGill Univ, Dept Oncol, Program Canc Genet, Montreal, PQ, Canada [ 155 ] Univ Cambridge, Sch Med, Cambridge, England [ 156 ] Ctr Hosp Univ Quebec, Res Ctr, Quebec City, PQ, Canada [ 157 ] Univ Laval, Quebec City, PQ, Canada [ 158 ] Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England [ 159 ] BC Canc Agcy, Canc Control Res, Vancouver, BC, Canada [ 160 ] Oslo Univ Hosp, Radiumhosp, Inst Canc Res, Dept Genet, Oslo, Norway [ 161 ] Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway [ 162 ] Univ Oslo, Oslo Univ Hosp, Dept Clin Mol Biol, Oslo, Norway [ 163 ] Haukeland Hosp, Dept Gynecol & Obstet, N-5021 Bergen, Norway [ 164 ] Univ Bergen, Dept Clin Sci, Ctr Canc Biomarkers, Bergen, Norway [ 165 ] Rutgers Canc Inst New Jersey, New Brunswick, NJ USA [ 166 ] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA [ 167 ] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr,Vanderbilt Ingram Canc C, Div Epidemiol,Dept Med, 221 Kirkland Hall, Nashville, TN 37235 USA [ 168 ] Univ Oulu, Dept Clin Chem, Lab Canc Genet & Tumor Biol, Oulu, Finland [ 169 ] Univ Oulu, Bioctr Oulu, Oulu, Finland [ 170 ] Northern Finland Lab Ctr Nordlab, Lab Canc Genet & Tumor Biol, Oulu, Finland [ 171 ] Erasmus Univ, Med Ctr, Dept Surg Oncol, Rotterdam, Netherlands [ 172 ] Erasmus Univ, Med Ctr, Dept Clin Genet, Family Canc Clin, Rotterdam, Netherlands [ 173 ] Mt Sinai Hosp, Lunenfeld Res Inst, Ontario Canc Genet Network, Fred A Litwin Ctr Canc Genet, Toronto, ON M5G 1X5, Canada [ 174 ] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada [ 175 ] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada [ 176 ] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON, Canada [ 177 ] Univ Toronto, Womens Coll, Res Inst, Toronto, ON, Canada [ 178 ] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands [ 179 ] Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands [ 180 ] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA [ 181 ] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA [ 182 ] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England [ 183 ] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden [ 184 ] Univ Glasgow, Beatson Inst Canc Res, Wolfson Wohl Canc Res Ctr, Inst Canc Sci, Glasgow, Lanark, Scotland [ 185 ] Glasgow Royal Infirm, Dept Gynaecol Oncol, Glasgow G4 0SF, Lanark, Scotland [ 186 ] Beatson West Scotland Canc Ctr, Canc Res UK Clin Trials Unit, Glasgow, Lanark, Scotland [ 187 ] Hong Kong Sanat & Hosp, Canc Genet Ctr, Hong Kong Hereditary Breast Canc Family Registry, Hong Kong, Hong Kong, Peoples R China [ 188 ] Univ Hong Kong, Dept Surg, Hong Kong, Hong Kong, Peoples R China [ 189 ] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea [ 190 ] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul, South Korea [ 191 ] Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul, South Korea [ 192 ] Sime Darby Med Ctr, Canc Res Initiat Fdn, Subang Jaya, Selangor, Malaysia [ 193 ] Univ Malaya, Med Ctr, Fac Med, Canc Res Inst, Kuala Lumpur, Malaysia [ 194 ] Aichi Canc Ctr Res Inst, Div Mol Med, Nagoya, Aichi, Japan [ 195 ] Aichi Canc Ctr Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi, Japan [ 196 ] Univ Malaya, Med Ctr, Dept Obstet & Gynecol, Kuala Lumpur, Malaysia [ 197 ] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China [ 198 ] Masaryk Mem Canc Inst & Med Fac, Brno, Czech Republic [ 199 ] Med Univ Vienna, Dept Obstet & Gynecol, Vienna, Austria [ 200 ] Med Univ Vienna, Ctr Comprehens Canc, Vienna, Austria [ 201 ] Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel [ 202 ] Carmel Hosp, Clalit Natl Israeli Canc Control Ctr, Haifa, Israel [ 203 ] Carmel Hosp, Dept Community Med & Epidemiol, Haifa, Israel [ 204 ] B Rappaport Fac Med, Haifa, Israel [ 205 ] NN Petrov Inst Oncol, St Petersburg, Russia [ 206 ] NorthShore Univ Hlth Syst, Ctr Med Genet, Evanston, IL USA [ 207 ] Univ Chicago, Med Ctr, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA [ 208 ] Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med, Div Human Genet, Columbus, OH 43210 USA [ 209 ] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary [ 210 ] Dartmouth Coll, Geisel Sch Med, Sect Biostat & Epidemiol, Dept Community & Family Med, Hanover, NH 03755 USA [ 211 ] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA [ 212 ] Duke Canc Inst, Canc Control & Populat Sci, Durham, NC USA [ 213 ] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, NL-6525 ED Nijmegen, Netherlands [ 214 ] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Mol Life Sci, Dept Gynaecol, NL-6525 ED Nijmegen, Netherlands [ 215 ] Univ New Mexico, Dept Internal Med, Div Epidemiol & Biostat, Albuquerque, NM 87131 USA [ 216 ] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA [ 217 ] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA [ 218 ] Lund Univ, Dept Oncol, Lund, Sweden [ 219 ] Sahlgrens Univ Hosp, Dept Clin Genet, Gothenburg, Sweden [ 220 ] Fred Hutchinson Canc Res Ctr, Program Epidemiol, 1124 Columbia St, Seattle, WA 98104 USA [ 221 ] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA [ 222 ] Univ Lund Hosp, Ctr Oncol, Reg Tumour Registry, S-22185 Lund, Sweden [ 223 ] Univ Sheffield, Sheffield Canc Res Dept Oncol, Sheffield, S Yorkshire, England [ 224 ] Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield, S Yorkshire, England [ 225 ] Pontificia Univ Javeriana, Inst Human Genet, Bogota, Colombia [ 226 ] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland [ 227 ] Landspitali Univ Hosp, Reykjavik, Iceland Organization-Enhanced Name(s) Landspitali National University Hospital [ 228 ] Univ Iceland, Sch Med, Reykjavik, Iceland [ 229 ] Maria Sklodowska Curie Mem Canc Ctr, Dept Pathol & Lab Diagnost, Warsaw, Poland [ 230 ] Inst Oncol, Warsaw, Poland [ 231 ] Natl Ctr Sci Res Demokritos, Mol Diagnost Lab, Inst Nucl & Radiol Sci & Technol, Energy & Safety, Athens, Greece [ 232 ] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA

Subjects
0301 basic medicine, Oncology, Male, Cancer Research, endocrine system diseases, LOCI, Estrogen receptor, FAMILY-HISTORY, Prostate cancer, 0302 clinical medicine, Ovarian Neoplasms/pathology, Prostate, Risk Factors, Brjóstakrabbamein, Odds Ratio, skin and connective tissue diseases, Ovarian Neoplasms, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Prostatic Neoplasms/genetics, Research Support, Non-U.S. Gov't, SINGLE-NUCLEOTIDE POLYMORPHISMS, Middle Aged, BRCA2 Protein/genetics, PANCREATIC-CANCER, 3. Good health, SUSCEPTIBILITY GENE, medicine.anatomical_structure, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, Codon, Terminator, Female, Risk Factors Substances, Adult, medicine.medical_specialty, Heterozygote, Breast Neoplasms, Blöðruhálskirtilskrabbamein, Breast Neoplasms/genetics, Biology, Polymorphism, Single Nucleotide, Risk Assessment, Article, Ovarian Neoplasms/genetics, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Research Support, N.I.H., Extramural, Internal medicine, Pancreatic cancer, Krabbameinsrannsóknir, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Neoplasm Invasiveness, Lysine/genetics, Krabbamein, Aged, Gynecology, BRCA2 Protein, Proportional hazards model, Lysine, DNA RECOMBINATION, CONSORTIUM, GERM-LINE MUTATION, Prostatic Neoplasms, Odds ratio, Arfgengi, medicine.disease, ESTROGEN-RECEPTOR, 030104 developmental biology, Logistic Models, PTT12, Eggjastokkar, FANCONI-ANEMIA, Ovarian cancer
Abstract

Contains fulltext : 172007.pdf (Publisher’s version ) (Closed access) BACKGROUND: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. METHODS: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. RESULTS: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10(-) (6)) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10(-3)). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10(-5) and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10(-5), respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. CONCLUSIONS: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations.

Published
2016
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7. Caspase-8 inhibition represses initial human monocyte activation in septic shock model

Author

Johanna Rodhe, José Antonio Pérez-Simón, Teresa Caballero-Velázquez, Luis Ignacio Sánchez-Abarca, Antonio J. Herrera, José L. Venero, Alejandro Carrillo-Jimenez, P Vlachos, Maria Jose Oliva-Martin, Bertrand Joseph, Albert García-Quintanilla, Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular, Ministerio de Economía y Competitividad (España), European Commission, Swedish Research Council, Swedish Childhood Cancer Foundation, Swedish Cancer Society, Swedish Parkinson Foundation, Swedish Brain Foundation, [Jose Oliva-Martin, Maria] Univ Seville, Fac Pharm, Dept Biochem & Mol Biol, Seville, Spain, [Carrillo-Jimenez, Alejandro] Univ Seville, Fac Pharm, Dept Biochem & Mol Biol, Seville, Spain, [Jose Herrera, Antonio] Univ Seville, Fac Pharm, Dept Biochem & Mol Biol, Seville, Spain, [Garcia-Quintanilla, Albert] Univ Seville, Fac Pharm, Dept Biochem & Mol Biol, Seville, Spain, [Luis Venero, Jose] Univ Seville, Fac Pharm, Dept Biochem & Mol Biol, Seville, Spain, [Jose Oliva-Martin, Maria] Univ Seville, CSIC, Inst Biomed Sevilla IBiS, Seville, Spain, [Rodhe, Johanna] Univ Seville, CSIC, Inst Biomed Sevilla IBiS, Seville, Spain, [Vlachos, Pinelopi] Univ Seville, CSIC, Inst Biomed Sevilla IBiS, Seville, Spain, [Joseph, Bertrand] Univ Seville, CSIC, Inst Biomed Sevilla IBiS, Seville, Spain, [Jose Oliva-Martin, Maria] Karolinska Inst, Canc Ctr Karolinska, Dept Oncol Pathol, Stockholm, Sweden, [Sanchez-Abarca, Luis Ignacio] Karolinska Inst, Canc Ctr Karolinska, Dept Oncol Pathol, Stockholm, Sweden, [Caballero-Velazquez, Teresa] Karolinska Inst, Canc Ctr Karolinska, Dept Oncol Pathol, Stockholm, Sweden, [Perez-Simon, Jose Antonio] Karolinska Inst, Canc Ctr Karolinska, Dept Oncol Pathol, Stockholm, SwedenHosp Univ Virgen del Rocio, Dept Haematol, Malaga, Spain, MINECO/FEDER, UE, Junta of Andalucia, and Swedish Cancer Foundation

Subjects
0301 basic medicine, Monocyte, Monocytes, caspase-8, sepsis, Mice, Mechanisms, Il-1-beta, Cells, Cultured, Caspase, Mice, Knockout, Caspase 8, biology, Pro-inflammatory activation, Switch, Caspase Inhibitors, Shock, Septic, Cell biology, medicine.anatomical_structure, Oncology, Necroptosis, monocyte, Cytokines, medicine.symptom, Cell activation, Caspase-8, Programmed cell death, Macrophage differentiation, necroptosis, Inflammation, 03 medical and health sciences, Sepsis, Pathology Section, medicine, Animals, Humans, Septic shock, medicine.disease, Research Paper: Pathology, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, inflammation, Immunology, biology.protein, Surviving sepsis, Cell-death
Abstract

In septic patients, the onset of septic shock occurs due to the over-activation of monocytes. We tested the therapeutic potential of directly targeting innate immune cell activation to limit the cytokine storm and downstream phases. We initially investigated whether caspase-8 could be an appropriate target given it has recently been shown to be involved in microglial activation. We found that LPS caused a mild increase in caspase-8 activity and that the caspase-8 inhibitor IETD-fmk partially decreased monocyte activation. Furthermore, caspase-8 inhibition induced necroptotic cell death of activated monocytes. Despite inducing necroptosis, caspase-8 inhibition reduced LPS-induced expression and release of IL-1β and IL-10. Thus, blocking monocyte activation has positive effects on both the pro and anti-inflammatory phases of septic shock. We also found that in primary mouse monocytes, caspase-8 inhibition did not reduce LPS-induced activation or induce necroptosis. On the other hand, broad caspase inhibitors, which have already been shown to improve survival in mouse models of sepsis, achieved both. Thus, given that monocyte activation can be regulated in humans via the inhibition of a single caspase, we propose that the therapeutic use of caspase-8 inhibitors could represent a more selective alternative that blocks both phases of septic shock at the source., This work was supported by grants SAF2012-39029 and SAF2015-64171R (MINECO/FEDER, UE), the Junta of Andalucía (P10-CTS-6494), the Swedish Research Council, the Swedish Childhood Cancer Foundation, the Swedish Cancer Foundation, Swedish Parkinson Foundation and the Swedish Brain Foundation.

Published
2016

8. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

Author

Laura J. Scott, Neil Robertson, Anders Hamsten, Domenico Palli, Susanne Moebus, Bernhard O. Boehm, Gunnar Sigurðsson, Paul W. Franks, C. N. A. Palmer, Sonali Pechlivanis, Katharine R. Owen, Michael E. Reschen, Sarah Edkins, Jason Carey, Christopher A. O’Callaghan, Norman Klopp, Caroline S. Fox, Petter Storm, N. William Rayner, Johan G. Eriksson, Thomas Illig, Anubha Mahajan, Erik Ingelsson, Allan Linneberg, Andrew R. Wood, Oddgeir L. Holmen, Nicola L. Beer, Mark I. McCarthy, Frank B. Hu, Peter Almgren, Heiner Boeing, Peter Donnelly, Carl Platou, Veikko Salomaa, Karl-Heinz Jöcke, Wen-Hong L. Kao, Lori L. Bonnycastle, Denis Rybin, Benjamin F. Voight, Peter Kraft, Inês Barroso, Claudia Langenberg, Teresa Ferreira, Peter Kovacs, Anne Raimondo, Christian Theil Have, Ulf de Faire, Torben Hansen, Han Chen, James B. Meigs, Timothy M. Frayling, Noël P. Burtt, Gerald Steinbach, Eric Boerwinkle, Michael Stumvoll, Stefan Gustafsson, Lars Lind, Andrew D. Morris, Alena Stančáková, Panagiotis Deloukas, Kari Stefansson, Augustine Kong, Hans A. Kestler, Andrew T. Hattersley, Beverley Balkau, Lorenzo Pasquali, Yingchang Lu, Nicola D. Kerrison, George B. Grant, Eeva Korpi-Hyövälti, Steven Wiltshire, Karl Gertow, Jorge Ferrer, Barbara Thorand, Inga Prokopenko, Matthias Blüher, Yvonne T. van der Schouw, Olga McLeod, Oluf Pedersen, Leena Peltonen, Anil Chalisey, Eleftheria Zeggini, Joseph Trakalo, Eric J.G. Sijbrands, Rainer Rauramaa, Guillaume Charpentier, Satu Männistö, Cordelia Langford, Lewin Eisele, Damiano Baldassarre, Lennart C. Karssen, Rona J. Strawbridge, Ghazala Mirza, Peter S. Chines, Roman Wennauer, Sara M. Willems, Erwin P. Bottinger, Timo Saaristo, Stéphane Cauchi, Ching-Ti Liu, Martijn van de Bunt, Valgerdur Steinthorsdottir, David Altshuler, Hyun Min Kang, Michael Boehnke, Jaakko Tuomilehto, Peter M. Nilsson, Kyle J. Gaulton, Jian'an Luan, Loic Yengo, David Couper, Reedik Mägi, Harald Grallert, Simone Wahl, Juha Saltevo, Phoenix Kwan, Cecilia M. Lindgren, Peter Lichtner, Richard N. Bergman, Andrew Crenshaw, João Fadista, Michael Roden, Annette Peters, Robert A. Scott, Unnur Thorsteinsdottir, James S. Pankow, Yeji Lee, Cornelia M. van Duijn, Samuli Ripatti, Francis S. Collins, Stéphane Lobbens, Niels Grarup, Ruth J. F. Loos, Julia Meyer, Marit E. Jørgensen, Christian Herder, Inger Njølstad, John R. B. Perry, Markus M. Nöthen, Man Li, Martina Müller-Nurasyid, Valeriya Lyssenko, Pierre Fontanillas, Michael D. Linderman, Leena Kinnunen, Jana K. Rundle, Elena Tremoli, Marilyn C. Cornelis, Tanya M. Teslovich, Todd Green, Raimund Erbel, Elisabeth M. van Leeuwen, Bengt Sennblad, Olle Melander, Sirkka Keinänen-Kiukaanniemi, Markku Laakso, Eero Lindholm, Alex S. F. Doney, Anke Tönjes, Maija Hassinen, Thomas W. Mühleisen, Gonçalo R. Abecasis, Nancy L. Pedersen, Thomas Sparsø, Johanna Kuusisto, Dorothée Thuillier, Qi Sun, Ian Dunham, Himanshu Chheda, Adam E. Locke, Philippe Froguel, Nicholas J. Wareham, Bruna Gigante, Jose C. Florez, Mozhgan Dorkhan, Omri Gottesman, Liming Liang, Anna Jonsson, Tiinamaija Tuomi, Leif Groop, Steve E. Humphries, Heikki A. Koistinen, Kristian Hveem, Astradur B. Hreidarsson, Jason Flannick, Torben Jørgensen, Clement Ma, Mattias Frånberg, Ewan Birney, Andrew P. Morris, Timo A. Lakka, Rob M. van Dam, Heather M. Stringham, Christian Gieger, Elodie Eury, Konstantin Strauch, Anna L. Gloyn, Rafn Benediktsson, Andres Metspalu, David J. Hunter, Karen L. Mohlke, Gudmar Thorleifsson, Josée Dupuis, Emmi Tikkanen, Christian Fuchsberger, Evelin Mihailov, Christopher J. Groves, Soren K. Thomsen, Tõnu Esko, Anne U. Jackson, Karin Leander, Douglas M. Ruderfer, Nikolay Oskolkov, Sekar Kathiresan, Robert Sladek, Lu Qi, Jasmina Kravic, Carmen Navarro, Epidemiology, Dermatology, Internal Medicine, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Cardiology, Wellcome Trust, Imperial College Healthcare NHS Trust- BRC Funding, Medical Research Council (MRC), [ 1 ] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England [ 2 ] Stanford Univ, Dept Genet, Stanford, CA 94305 USA [ 3 ] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA [ 4 ] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England [ 5 ] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia [ 6 ] Univ Oxford, Nuffield Dept Med, Ctr Cellular & Mol Physiol, Oxford, England [ 7 ] Wellcome Trust Sanger Inst, Hinxton, England [ 8 ] Univ Cambridge, Sch Clin Med, Inst Metab Sci, Med Res Council MRC Epidemiol Unit, Cambridge, England [ 9 ] Univ London Imperial Coll Sci Technol & Med, Genom Common Dis, London, England [ 10 ] Broad Inst Harvard & MIT, Cambridge, MA USA [ 11 ] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark [ 12 ] European Genom Inst Diabet, Lille Inst Biol, Lille, France [ 13 ] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany [ 14 ] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany [ 15 ] German Ctr Diabet Res, Neuherberg, Germany [ 16 ] Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden [ 17 ] Sci Life Lab, Stockholm, Sweden [ 18 ] Stockholm Univ, Dept Numer Anal & Comp Sci, S-10691 Stockholm, Sweden [ 19 ] Fritz Lipmann Inst, Leibniz Inst Age Res, Jena, Germany [ 20 ] Univ Ulm, Med Syst Biol, D-89069 Ulm, Germany [ 21 ] Finnish Inst Mol Med, Helsinki, Finland [ 22 ] Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany [ 23 ] Uppsala Univ, Dept Med Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden [ 24 ] deCODE Genet Amgen Inc, Reykjavik, Iceland [ 25 ] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA [ 26 ] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA [ 27 ] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA [ 28 ] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA [ 29 ] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA [ 30 ] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands [ 31 ] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA [ 32 ] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA [ 33 ] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA [ 34 ] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA [ 35 ] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA [ 36 ] Univ Penn, Perelman Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA [ 37 ] Lund Univ, Scania Univ Hosp, Dept Clin Sci Malmo, Ctr Diabet, Malmo, Sweden [ 38 ] IRCCS, Ctr Cardiol Monzino, Milan, Italy [ 39 ] Univ Milan, Dipartimento Sci Farmacol & Biomol, Milan, Italy [ 40 ] Ctr Rech Epidemiol & Sante Populat CESP, INSERM, U1018, Villejuif, France [ 41 ] Univ Paris 11, UMRS 1018, Villejuif, France [ 42 ] Univ Iceland, Fac Med, Reykjavik, Iceland [ 43 ] Landspitali Univ Hosp, Reykjavik, Iceland Organization-Enhanced Name(s) Landspitali National University Hospital [ 44 ] Univ Leipzig, Integrated Treatment & Res IFB Ctr Adipos Dis, D-04109 Leipzig, Germany [ 45 ] Univ Leipzig, Dept Med, D-04109 Leipzig, Germany [ 46 ] German Inst Human Nutr, Potsdam, Germany [ 47 ] NHGRI, US NIH, Bethesda, MD 20892 USA [ 48 ] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA [ 49 ] Corbeil Essonnes Hosp, Endocrinol Diabetol Unit, Corbeil Essonnes, France [ 50 ] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA [ 51 ] Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA [ 52 ] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore [ 53 ] Univ Dundee, Ninewells Hosp, Biomed Res Inst, Ctr Diabet Res, Dundee, Scotland [ 54 ] Univ Dundee, Ninewells Hosp, Biomed Res Inst, Pharmacogen Ctr, Dundee, Scotland [ 55 ] Lund Univ, Ctr Diabet, Dept Clin Sci Malmo, Novo Nordisk Scandinavia, Malmo, Sweden [ 56 ] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland [ 57 ] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland [ 58 ] Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki, Finland [ 59 ] Folkhalsan Res Ctr, Helsinki, Finland [ 60 ] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA [ 61 ] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA [ 62 ] CNRS, UMR 8199, Inst Biol, Lille, France [ 63 ] Univ Lille 2, Inst Pasteur, Lille, France [ 64 ] NHLBI, Framingham Heart Study, Framingham, MA USA [ 65 ] Brigham & Womens Hosp, Div Endocrinol & Metab, Boston, MA 02115 USA [ 66 ] Harvard Univ, Sch Med, Boston, MA USA [ 67 ] Lund Univ, Dept Clin Sci, Malmo, Sweden [ 68 ] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden [ 69 ] Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, S-10401 Stockholm, Sweden [ 70 ] Kuopio Res Inst Exercise Med, Kuopio, Finland [ 71 ] Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany [ 72 ] Partner Site Dusseldorf, German Ctr Diabet Res, Dusseldorf, Germany [ 73 ] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, Nord Trondelag Hlth Study HUNT Res Ctr, Levanger, Norway [ 74 ] UCL, Inst Cardiovasc Sci, British Heart Fdn BHF Labs, Cardiovasc Genet, London, England [ 75 ] Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA [ 76 ] Steno Diabet Ctr, DK-2820 Gentofte, Denmark [ 77 ] Capital Reg Denmark, Res Ctr Prevent & Hlth, Copenhagen, Denmark [ 78 ] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark [ 79 ] Aalborg Univ, Fac Med, Aalborg, Denmark [ 80 ] Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany [ 81 ] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany [ 82 ] Rigshosp, Copenhagen Univ Hosp, DK-2100 Copenhagen, Denmark [ 83 ] Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark [ 84 ] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany [ 85 ] Guys & St Thomas Natl Hlth Serv NHS Fdn Trust, Guys & St Thomas Hosp, Genom Core Facil, Biomed Res Ctr, London, England [ 86 ] Univ Bonn, Inst Human Genet, Bonn, Germany [ 87 ] Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany [ 88 ] Res Ctr Julich, Inst Neurosci & Med INM 1, Julich, Germany [ 89 ] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany [ 90 ] Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Neuherberg, Germany [ 91 ] Partner Site Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany [ 92 ] Inst Murciano Invest Biosanitaria Virgen de la Ar, Murcia Reg Hlth Council, Dept Epidemiol, Murcia, Spain [ 93 ] CIBERESP, Madrid, Spain [ 94 ] Univ Murcia, Dept Hlth & Social Sci, Murcia, Spain [ 95 ] Churchill Hosp, Biomed Res Ctr, Oxford Natl Inst Hlth Res, Oxford OX3 7LJ, England [ 96 ] Canc Res & Prevent Inst ISPO, Florence, Italy [ 97 ] Nord Trondelag Hlth Trust, Levanger Hosp, Dept Internal Med, Levanger, Norway [ 98 ] Univ Hosp Dusseldorf, Dept Endocrinol & Diabetol, Dusseldorf, Germany [ 99 ] Icahn Sch Med Mt Sinai, Dept Psychiat, Div Psychiat Genom, New York, NY 10029 USA [ 100 ] Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA [ 101 ] Univ Med Ctr Utrecht, Utrecht, Netherlands [ 102 ] Iceland Heart Assoc, Kopavogur, Iceland [ 103 ] Univ Eastern Finland, Dept Med, Kuopio, Finland [ 104 ] Kuopio Univ Hosp, SF-70210 Kuopio, Finland [ 105 ] Univ Ulm, Dept Clin Chem & Cent Lab, D-89069 Ulm, Germany [ 106 ] Univ Helsinki, Dept Publ Hlth, Hjelt Inst, Helsinki, Finland [ 107 ] Helsinki Univ Hosp, Abdominal Ctr, Dept Endocrinol, Helsinki, Finland [ 108 ] Univ Helsinki, Res Program Diabet & Obes, Helsinki, Finland [ 109 ] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands [ 110 ] Univ Exeter, Sch Med, Genet Complex Traits, Exeter, Devon, England [ 111 ] European Mol Biol Lab, EBI, Hinxton, England [ 112 ] Germans Trias & Pujol Univ Hosp & Res Inst, Div Endocrinol, Badalona, Spain [ 113 ] Josep Carreras Leukaemia Res Inst, Badalona, Spain [ 114 ] CIBERDEM, Barcelona, Spain [ 115 ] Univ London Imperial Coll Sci Technol & Med, Dept Med, London, England [ 116 ] Inst Invest Biomed August Pi & Sunyer, Ctr Esther Koplowitz, Barcelona, Spain [ 117 ] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA [ 118 ] Harvard Univ, Sch Med, Dept Med, Boston, MA USA [ 119 ] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA [ 120 ] Massachusetts Gen Hosp, Diabet Res Ctr, Boston, MA 02114 USA [ 121 ] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Houston, TX 77030 USA [ 122 ] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA [ 123 ] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA [ 124 ] Netherlands Consortium Hlth Ageing, Netherlands Genom Initiat, Rotterdam, Netherlands [ 125 ] Ctr Med Syst Biol, Rotterdam, Netherlands [ 126 ] Massachusetts Gen Hosp, Gen Med Div, Boston, MA 02114 USA [ 127 ] Univ Eastern Finland, Inst Biomed Physiol, Kuopio, Finland [ 128 ] Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, SF-70210 Kuopio, Finland [ 129 ] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden [ 130 ] Univ Uppsala Hosp, Dept Med Sci, Uppsala, Sweden [ 131 ] Univ Oulu, Inst Hlth Sci, Fac Med, Oulu, Finland [ 132 ] Oulu Univ Hosp, Unit Gen Practice, Oulu, Finland [ 133 ] South Ostrobothnia Cent Hosp, Seinajoki, Finland [ 134 ] Finnish Diabet Assoc, Tampere, Finland [ 135 ] Pirkanmaa Dist Hosp, Tampere, Finland [ 136 ] Cent Finland Cent Hosp, Dept Med, Jyvasklya, Finland [ 137 ] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia [ 138 ] Univ Duisdurg Essen, Univ Hosp Essen, West German Heart Ctr, Clin Cardiol, Essen, Germany [ 139 ] Natl Inst Hlth & Welf, Publ Hlth Genom Unit, Helsinki, Finland [ 140 ] Univ Med Ctr Ulm, Dept Internal Med, Div Endocrinol & Diabet, Ulm, Germany [ 141 ] Univ London Imperial Coll Sci Technol & Med, Lee Kong Chian Sch Med, London SW7 2AZ, England [ 142 ] Nanyang Technol Univ, Singapore 639798, Singapore [ 143 ] Cedars Sinai Med Ctr, Diabet & Obes Res Inst, Los Angeles, CA 90048 USA [ 144 ] Univ N Carolina, Dept Genet, Chapel Hill, NC USA [ 145 ] Univ Helsinki, Cent Hosp, Dept Med, Div Endocrinol, Helsinki, Finland [ 146 ] Minerva Fdn, Helsinki, Finland [ 147 ] Hosp Univ La Paz, Inst Invest Sanitaria, Madrid, Spain [ 148 ] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria [ 149 ] King Abdulaziz Univ, Diabet Res Grp, Jeddah 21413, Saudi Arabia [ 150 ] Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway [ 151 ] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England [ 152 ] Univ Oxford, Dept Stat, Oxford OX1 3TG, England [ 153 ] Univ Exeter, Sch Med, Inst Biomed & Clin Sci, Exeter, Devon, England [ 154 ] Ctr Hosp Univ Montreal, Ctr Rech, Montreal Diabet Res Ctr, Montreal, PQ, Canada [ 155 ] McGill Univ, Montreal, PQ, Canada [ 156 ] Genome Quebec Innovat Ctr, Montreal, PQ, Canada [ 157 ] Univ Southern Denmark, Fac Hlth Sci, Odense, Denmark [ 158 ] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland [ 159 ] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA [ 160 ] Univ Cambridge, Metab Res Labs, Wellcome Trust MRC Inst Metab Sci, Cambridge, England [ 161 ] Cambridge Biomed Res Ctr, Natl Inst Hlth Res, Cambridge, England [ 162 ] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA [ 163 ] Harvard Univ, Sch Med, Dept Mol Biol, Boston, MA USA [ 164 ] Univ Liverpool, Dept Biostat, Liverpool L69 3BX, Merseyside, England [ 165 ] Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool L69 3BX, Merseyside, England, Luan, Jian'an [0000-0003-3137-6337], Perry, John [0000-0001-6483-3771], Barroso, Ines [0000-0001-5800-4520], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository

Subjects
endocrine system diseases, Medizin, Genome-wide association study, Glucose homeostasis, WIDE ASSOCIATION, Association mapping, Non-U.S. Gov't, Genome-Wide Association Study, Regulation of gene expression, Genetics, Genetics & Heredity, LARGE-SCALE ASSOCIATION, Research Support, Non-U.S. Gov't, COMMON VARIANTS, Chromosome Mapping, 11 Medical And Health Sciences, Genomics, 3. Good health, TRANSCRIPTION FACTORS, Liver, Hepatocyte Nuclear Factor 3-beta, Medical Genetics, Life Sciences & Biomedicine, Chromatin Immunoprecipitation, endocrine system, European Continental Ancestry Group/genetics, Biology, GENOTYPE IMPUTATION, Research Support, INSULIN-SECRETION, Polymorphism, Single Nucleotide, Article, N.I.H, Sykursýki, Islets of Langerhans, SDG 3 - Good Health and Well-being, Research Support, N.I.H., Extramural, HUMAN PANCREATIC-ISLETS, GLYCEMIC TRAITS, Journal Article, SNP, Humans, Genetic Predisposition to Disease, Comparative Study, Enhancer, Medicinsk genetik, Science & Technology, Binding Sites, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Receptor, Melatonin, MT2, Extramural, Molecular Sequence Annotation, Arfgengi, 06 Biological Sciences, Genetic Predisposition to Disease/genetics, BETA-CELL, Diabetes Mellitus, Type 2/genetics, Diabetes Mellitus, Type 2, Gene Expression Regulation, Genetic Loci, Case-Control Studies, Gene-Environment Interaction, GLUCOSE-HOMEOSTASIS, Chromatin immunoprecipitation, Developmental Biology
Abstract

To access publisher's full text version of this article click on the hyperlink at the bottom of the page We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease. cademy of Finland 77299 102318 10493 118065 123885 124243 129293 129680 136895 139635 211119 213506 251217 263836 Agence National de la Recherche Association de Langue Francaise pour l'Etude du Diabete et des Maladies Metaboliques Association Diabeete Risque Vasculaire Association Francaise des Diabetiques Association of Danish Pharmacies Augustinus Foundation Becket Foundation British Diabetes Association (BDA) Research British Heart Foundation Central Norway Health Authority Central Finland Hospital District Center for Inherited Disease Research (CIDR) City of Kuopio City of Leutkirch Copenhagen County Danish Centre for Evaluation and Health Technology Assessment Danish Council for Independent Research Danish Heart Foundation Danish Research Councils Deutsche Forschungsgemeinschaft ER 155/6-2 Diabetes Research Foundation Diabetes UK Doris Duke Charitable Foundation Erasmus Medical Center Erasmus University Estonian government SF0180142s08 European Commission ENGAGE HEALTH-F4-2007-201413 FP7-201413 FP7-245536 EXGENESIS LSHM-CT-2004-005272 FP6 LSHM_CT_2006_037197 LSHM-CT-2007-037273 C-Public Health 2004310 European Regional Development Fund Federal Ministry of Education and Research, Germany FKZ 01GI1128 FKZ 01EO1001 Federal Ministry of Health, Germany Finnish Diabetes Association Finnish Diabetes Research Foundation Finnish Foundation for Cardiovascular Research Finnish Medical Society Folkhalsan Research Foundation Foundation for Life and Health in Finland Foundation for Old Servants Fredrick och Ingrid Thuring Foundation French region of Nord-Pas-de-Calais (Contrat de Projets Etat-Region) German Center for Diabetes Research German Research Council GRK1041 German National Genome Research Network Groupe d'Etude des Maladies Metaboliques et Systemiques Health Care Centers in Vasa, Narpes and Korsholm, Finland Health Foundation Heinz Nixdorf Foundation Helmholtz Zentrum Munchen Helsinki University Central Hospital Research Foundation Hospital District of Southwest Finland Ib Henriksens Foundation IngaBritt and Arne Lundberg's Research Foundation 359 Karolinska Institutet Knut and Alice Wallenberg Foundation KAW 2009.0243 Kuopio University Hospital Lundbeck Foundation Magnus Bergvall Foundation Medical Faculty of University Duisburg-Essen Medical Research Council, UK G0000649 G0601261 Ministry for Health, Welfare and Sports, the Netherlands Ministry of Education and Culture, Finland 722 627 Ministry of Education, Culture and Science, the Netherlands Ministry of Health and Prevention, Denmark Ministry of Social Affairs and Health, Finland Ministry of Innovation, Science, Research and Technology of North Rhine-Westphalia, Germany Munich Center of Health Sciences Municipal Health Care Center and Hospital in Jakobstad, Finland municipality of Rotterdam, the Netherlands Narpes Health Care Foundation National Health Screening Service of Norway National Heart, Lung, and Blood Institute, USA HHSN268201100005C HHSN268201100006C HHSN268201100007C HHSN268201100008C HHSN268201100009C HHSN268201100010C HHSN268201100011C HHSN268201100012C N01HC25195 N02HL64278 R01HL087641 R01HL59367 R01HL086694 National Human Genome Research Institute, USA U01HG004402 N01HG65403 National Institute for Diabetes and Digestive and Kidney Diseases, USA R01DK078616 U01DK085526 K24DK080140 R01DK073490 National Institute for Health and Welfare, Finland National Institutes of Health, USA HHSN268200625226C UL1RR025005 R01DK062370 R01DK072193 1Z01HG000024 AG028555 AG08724 AG04563 AG10175 AG08861 U01HG004399 DK58845 CA055075 DK085545 DK098032 Netherlands Genomics Initiative Netherlands Organisation for Health Research and Development Netherlands Organisation of Scientific Research NOW Investments 175.010.2005.011 911-03-012 050-060-810 Nord-Trondelag County Council Nordic Center of Excellence in Disease Genetics Norwegian Institute of Public Health Norwegian Research Council Novo Nordisk Foundation Ollquist Foundation Oxford National Institute for Health Research (NIHR) Biomedical Research Centre Paavo Nurmi Foundation Paivikki and Sakari Sohlberg Foundation Perklen Foundation Pirkanmaa Hospital District, Finland Programme Hospitalier de Recherche Clinique Programme National de Recherche sur la Diabete Research Institute for Diseases in the Elderly 014-93-015 Robert Dawson Evans Endowment, Department of Medicine, Boston University School of Medicine and Boston Medical Center Royal Swedish Academy of Sciences Sarstedt, Germany Signe and Ane Gyllenberg Foundation Sigrid Juselius Foundation Slottery Machine Association, Finland Social Insurance Institution of Finland South OstroBothnia Hospital District state of Baden-Wurttemberg, Germany Stockholm County Council 560183 Swedish Cultural Foundation, Finland Swedish Diabetes Foundation Swedish e-science Research Center Swedish Foundation for Strategic Research Swedish Heart-Lung Foundation Swedish Research Council SFO EXODIAB 2009-1039 521-2010-3490 521-2007-4037 521-2008-2974 ANDIS 825-2010-5983 LUDC 349-2008-6589 8691 Swedish Society of Medicine Tore Nilsson Foundation Torsten and Ragnar Soderbergs Stiftelser MT33/09 University Hospital Essen University of Tromso University College London NIHR Biomedical Research Centre UK NIHR Cambridge Biomedical Research Centre Uppsala University Uppsala University Hospital Vaasa Hospital District Velux Foundation Wellcome Trust GR072960 076113 083948 090367 090532 083270 086596 098017 095101 098051 098381

Published
2015
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9. Health-related quality of life in food-allergic adults from eight European countries

Author

Bertine M. J. Flokstra-de Blok, Peter Burney, Marek L. Kowalski, E. J. Duiverman, Monteserrat Fernandéz-Rivas, Paweł Starosta, Ewa Rokicka, Belén de la Hoz Caballer, Nikos Papadopoulos, Sonia Vásquez-Cortés, Lynn J. Frewer, N. J. Goossens, Monica Jedrzejczak-Czechowicz, Marianne Heibert Arnlind, Anthony E.J. Dubois, L. Barreales, Ricardo Asero, Sven-Arne Jansson, Gerbrich N. van der Meulen, André C. Knulst, Michael Clausen, Ashok Purohit, Imnaculada Cerecedo, Groningen Research Institute for Asthma and COPD (GRIAC), and [ 1 ] Univ Groningen, Univ Med Ctr Groningen, Dept Pediat Pulmonol & Pediat Allergy, Groningen, Netherlands [ 2 ] Univ Groningen, Univ Med Ctr Groningen, GRIAC Res Inst, Groningen, Netherlands [ 3 ] Univ Groningen, Univ Med Ctr Groningen, Dept Gen Practice, Groningen, Netherlands [ 4 ] Martini Hosp, Dept Pediat Allergy, Groningen, Netherlands [ 5 ] Karolinska Inst, Ctr Allergy Res, Stockholm, Sweden [ 6 ] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden [ 7 ] Clin San Carlo, Ambulatorio Allergol, Paderno Dugnano, Italy [ 8 ] Hosp Clin San Carlos, IdISSC, Res Unit, Dept Prevent Med, Madrid, Spain [ 9 ] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Dept Resp Epidemiol & Publ Hlth, London, England [ 10 ] Hosp Univ Sureste, Secc Alergol, Madrid, Spain [ 11 ] Univ Hosp, Landspitali, Dept Allergy, Reykjavik, Iceland [ 12 ] Hosp Clin San Carlos, IdISSC, Dept Allergy, Madrid, Spain [ 13 ] Food Safety & Consumer Behav, Mkt & Consumer Behaviour Grp, Wageningen, Netherlands [ 14 ] Newcastle Univ, SAFRD, CRE, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England [ 15 ] Hosp Ramon & Cajal, Dept Allergy, E-28034 Madrid, Spain [ 16 ] Med Univ Lodz, Dept Immunol Rheumatol & Allergy, Lodz, Poland [ 17 ] Univ Med Ctr Utrecht, Dept Dermatol Allergol, Utrecht, Netherlands [ 18 ] Univ Athens, Dept Allergy, Pediat Clin 2, Athens, Greece [ 19 ] Univ Strasbourg, Univ Hosp, Dept Chest Dis, Div Allergy, Strasbourg, France [ 20 ] Univ Lodz, Fac Econ & Sociol, PL-90131 Lodz, Poland

Subjects
Pulmonary and Respiratory Medicine, Quality of Life/psychology, Adult, Male, Pediatrics, medicine.medical_specialty, Food Hypersensitivity/pathology, Fæðuofnæmi, Immunology, QUESTIONNAIRE, CHILDREN, Lífsgæði, DISEASE, Quality of life (healthcare), Questionnaires/standards, Cronbach's alpha, Food allergy, Environmental health, Internal consistency, Surveys and Questionnaires, medicine, Immunology and Allergy, Humans, UK, Community survey, VALIDITY, Health related quality of life, business.industry, Food Hypersensitivity/psychology, Construct validity, Independent measure, Middle Aged, medicine.disease, humanities, PREVALENCE, Europe, Quality of Life, Female, business, Fæðuóþol, Food Hypersensitivity/immunology, BURDEN, METHODOLOGY, Food Hypersensitivity, FORM
Abstract

To access publisher's full text version of this article click on the hyperlink at the bottom of the page Food allergy can impair health-related quality of life (HRQL). Food Allergy Quality of Life Questionnaires (FAQLQs) have been developed and validated, including an adult form (FAQLQ-AF). HRQL has not, to date, been measured across different European countries using a uniform methodology. To translate and validate the FAQLQ-AF for use in 8 European countries (Iceland, The Netherlands, Poland, France, Spain, Italy, Greece, and Sweden). The English FAQLQ-AF was translated, back-translated, and compared for use in the 8 relevant European languages. Adults with a perceived food allergy were recruited from outpatient departments and through a community survey. Participants completed the FAQLQ-AF, the Food Allergy Independent Measure, and questions concerning participants' characteristics. Validity of the FAQLQ-AF was analyzed for use in the 8 countries. The FAQLQ-AF had strong construct validity (r > 0.59) and an excellent internal consistency (Cronbach α > 0.95) in all countries. Total FAQLQ-AF scores (range 3.2-5.0) were significantly different across participating countries. The FAQLQ-AF is a suitable and valid instrument for measuring HRQL in food-allergic adults in Iceland, The Netherlands, Poland, France, Spain, Italy, Greece, and Sweden. The impact of food allergy on HRQL seems to differ among adults from the 8 participating European countries. Stichting Astmabestrijding 2009/014 Centre for Allergy Research at Karolinska Institutet Swedish Asthma and Allergy Foundation Sahlgrenska University Hospital Sweden info:eu-repo/grantAgreement/EC/FP7/514000

Published
2014

10. Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis

Author

Carl A. Anderson, Konstantinos N. Lazaridis, Isabelle Cleynen, Wesley K. Thompson, Ole A. Andreassen, Andreas Teufel, Felix Braun, Einar Björnsson, John D. Rioux, Roger W. Chapman, Inke R. König, Javier Gutierrez-Achury, Gabriele Mayr, Stefan Schreiber, Stephan Brand, Mitja Mitrovic, Annika Bergquist, Michael P. Manns, Jean-Paul Achkar, Simon M. Rushbrook, Cyriel Y. Ponsioen, Martina Sterneck, Kirsten Muri Boberg, Christian Rust, Andrew J. Schork, Albert Parés, Gideon M. Hirschfield, Graeme J.M. Alexander, Espen Melum, Bertus Eksteen, Juliane Winkelmann, Cisca Wijmenga, Ingo Thomsen, Hanns-Ulrich Marschall, Isis Ricaño-Ponce, Erik Schrumpf, Peter J. P. Croucher, Jimmy Z. Liu, Richard H. Duerr, Nadezhda Tsankova Doncheva, Annarosa Floreani, Eva Ellinghaus, Markus M. Nöthen, Brian D. Juran, Judy H. Cho, Mario Albrecht, Stefan Herms, Tobias J. Weismüller, Leonid Padyukov, Virpi Leppa, Morten H. Vatn, Mark S. Silverberg, Tobias Müller, Olivier Chazouillères, Domenico Alvaro, Christoph Schramm, Ruslan Dorfman, Richard Sandford, David A. van Heel, Rinse K. Weersma, Suna Onengut-Gumuscu, Anders M. Dale, Martti Färkkilä, Brijesh Srivastava, Severine Vermeire, Trine Folseraas, Vito Annese, Pietro Invernizzi, Tejas Shah, Daniel Gotthardt, Janna Saarela, Christopher L. Bowlus, Sigrid Næss, Andrew Mason, Stephen S. Rich, Johannes R. Hov, Peter R. Durie, Andre Franke, Kristian Hveem, Tom H. Karlsen, Piotr Milkiewicz, Miquel Sans, Georgios N. Dalekos, David Ellinghaus, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Wellcome Trust Sanger Inst, Cambridge, England, Oslo Univ Hosp, Rikshosp, Div Canc Med Surg & Transplantat, Norwegian PSC Res Ctr,Dept Transplantat Med, Oslo, Norway Oslo Univ Hosp, Rikshosp, Internal Med Res Inst, KG Jebsen Inflammat Res Ctr, Oslo, Norway Univ Oslo, Inst Clin Med, Oslo, Norway Oslo Univ Hosp, Rikshosp, Div Canc Med Surg & Transplantat, Sect Gastroenterol,Dept Transplantat Med, Oslo, Norway Univ Kiel, Inst Clin Mol Biol, Kiel, Germany Dept Gastroenterol & Hepatol, Norfolk, VA USA Univ Hosp Natl Hlth Serv NHS Trust, Norwich, Norfolk, England Max Planck Inst Informat, D-66123 Saarbrucken, Germany Oslo Univ Hosp, Div Mental Hlth & Addict, KG Jebsen Ctr Psychosis Res, Oslo, Norway Univ Groningen, Dept Gastroenterol & Hepatol, Groningen, Netherlands Univ Groningen, Univ Med Ctr Groningen, NL-9713 AV Groningen, Netherlands Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, Hannover, Germany Hannover Med Sch, Integrated Res & Treatment Ctr Transplantat IFB T, Hannover, Germany Univ Calgary, Dept Med, Snyder Inst Chron Dis, Calgary, AB, Canada Humanitas Clin & Res Ctr, Ctr Autoimmune Liver Dis, Rozzano, Italy Univ Toronto, Dept Med, Div Gastroenterol, Toronto, ON, Canada NIHR, Liver Res Ctr, Biomed Res Unit, Birmingham, W Midlands, England Univ Heidelberg Hosp, Dept Med, Heidelberg, Germany Univ Barcelona, IDIBAPS, CIBERehd, Liver Unit,Hosp Clin, Barcelona, Spain Mayo Clin, Coll Med, Ctr Basic Res Digest Dis, Div Gastroenterol & Hepatol, Rochester, MN USA Pomeranian Med Univ, Liver Unit, Szczecin, Poland Pomeranian Med Univ, Liver Res Labs, Szczecin, Poland Univ Munich, Dept Med 2, Munich, Germany Univ Med Ctr Hamburg Eppendorf, Dept Med 1, Hamburg, Germany Charite, Dept Internal Med Hepatol & Gastroenterol, D-13353 Berlin, Germany Univ Cambridge, Acad Dept Med Genet, Cambridge, England Univ Thessaly, Sch Med, Dept Med, Larisa, Greece Univ Thessaly, Sch Med, Larisa, Greece Univ Bonn, Inst Human Genet, Bonn, Germany Univ Bonn, Dept Genom, Life & Brain Ctr, Bonn, Germany Tech Univ Munich, Inst Human Genet, D-80290 Munich, Germany Tech Univ Munich, Dept Neurol, D-80290 Munich, Germany German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany Univ Groningen, Dept Genet, Groningen, Netherlands Univ Med Ctr Schleswig Holstein, Dept Gen Visceral Thorac Transplantat & Pediat Su, Kiel, Germany Univ Amsterdam, Acad Med Ctr, Dept Gastroenterol & Hepatol, NL-1105 AZ Amsterdam, Netherlands Univ Calif Berkeley, Dept Environm Sci Policy & Management, Berkeley, CA 94720 USA Univ Med Ctr Hamburg Eppendorf, Dept Hepatobiliary Surg & Transplantat, Hamburg, Germany Johannes Gutenberg Univ Mainz, Dept Med 1, Mainz, Germany Univ Alberta, Div Gastroenterol & Hepatol, Edmonton, AB, Canada Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland Univ Helsinki, FIMM, Publ Hlth Genom Unit, Helsinki, Finland Natl Inst Hlth & Welf, Helsinki, Finland Hosp Sick Children, Program Genet & Genome Biol, Toronto, ON M5G 1X8, Canada Univ Roma La Sapienza, Dept Clin Med, Div Gastroenterol, Rome, Italy Univ Padua, Dept Surg Oncol & Gastroenterol Sci, Padua, Italy Univ Virginia, Div Endocrinol & Metab, Ctr Publ Hlth Genom, Charlottesville, VA USA Univ Virginia, Dept Internal Med, Div Endocrinol & Metab, Charlottesville, VA USA Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA Univ Calif San Diego, Grad Program Cognit Sci, La Jolla, CA 92093 USA Med Univ Lubeck, Inst Med Biometry & Stat, D-23538 Lubeck, Germany Norwegian Univ Sci & Technol, Fac Med, Dept Publ Hlth, N-7034 Trondheim, Norway Katholieke Univ Leuven, Dept Clin & Expt Med, Louvain, Belgium Queen Mary Univ London, Blizard Inst, Barts & London Sch Med & Dent, London, England Landspitali Univ Hosp, Dept Internal Med, Div Gastroenterol & Hepatol, Reykjavik, Iceland Hosp Sick Children, Physiol & Expt Med Res Inst, Toronto, ON M5G 1X8, Canada Akershus Univ Hosp, EpiGen, Nordbyhagen, Norway Mt Sinai Hosp, Inflammatory Bowel Dis IBD Grp, Zane Cohen Ctr Digest Dis, Toronto, ON M5G 1X5, Canada Univ Pittsburgh, Sch Med, Dept Med, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA 15213 USA Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden Karolinska Univ Hosp Solna, Stockholm, Sweden Univ Munich, Univ Hosp Munich Grosshadern, Dept Med 2, Munich, Germany Ctr Med Teknon, Dept Digest Dis, Barcelona, Spain Casa Sollievodella Sofferenza Hosp, Ist Ricovero & Cura Carattere Sci, Div Gastroenterol, San Giovanni Rotondo, Italy Azienda Osped Univ Careggi, Unit Gastroenterol SOD2, Florence, Italy Cleveland Clin, Dept Gastroenterol & Hepatol, Inst Digest Dis, Cleveland, OH 44106 USA Cleveland Clin, Lerner Res Inst, Dept Pathobiol, Cleveland, OH 44106 USA Sahlgrens Acad, Inst Med, Dept Internal Med, Gothenburg, Sweden Univ Hosp, Gothenburg, Sweden Univ Paris 06, Hop St Antoine, AP HP, Dept Hepatol, Paris, France Univ Calif Davis, Div Gastroenterol & Hepatol, Davis, CA 95616 USA Katholieke Univ Leuven Hosp, Dept Gastroenterol, Louvain, Belgium Univ Med Greifswald, Dept Bioinformat, Inst Biometr & Med Informat, Greifswald, Germany Univ Montreal, Res Ctr, Montreal, PQ, Canada Montreal Heart Inst, Res Ctr, Montreal, PQ H1T 1C8, Canada Univ Cambridge, Dept Med, Div Hepatol, Cambridge CB2 2QQ, England Karolinska Univ, Huddinge Hosp, Karolinska Inst, Dept Gastroenterol & Hepatol, Stockholm, Sweden Yale Univ, Dept Med, Sect Digest Dis, New Haven, CT 06520 USA Univ Kiel, Dept Gen Internal Med, Kiel, Germany Univ Kiel, Univ Hosp Schleswig Holstein, PopGen Biobank, Kiel, Germany Helsinki Univ Hosp, Dept Med, Div Gastroenterol, Helsinki, Finland Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA John Radcliffe Univ Hosp NHS Trust, Dept Hepatol, Oxford, England Univ Bergen, Dept Clin Med, Div Gastroenterol, Bergen, Norway, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Gastroenterology and Hepatology

Subjects
Linkage disequilibrium, HISTONE DEACETYLASE, Genotyping Techniques, endocrine system diseases, Genome-wide association study, Disease, Bioinformatics, Linkage Disequilibrium, 0302 clinical medicine, Gene Frequency, Risk Factors, Oligonucleotide Array Sequence Analysis, 0303 health sciences, Crohn's disease, education.field_of_study, digestive, oral, and skin physiology, CELIAC-DISEASE, Genetic Pleiotropy, Lifrarsjúkdómar, 3. Good health, FALSE DISCOVERY RATE, ULCERATIVE-COLITIS, genetic association study, disease genetics, 030211 gastroenterology & hepatology, SUSCEPTIBILITY LOCI, Population, Cholangitis, Sclerosing, Single-nucleotide polymorphism, Human leukocyte antigen, GENETIC RISK, Biology, liver, Polymorphism, Single Nucleotide, digestive system, Article, Primary sclerosing cholangitis, 03 medical and health sciences, FUNCTIONAL SIMILARITY, Genetics, medicine, Humans, GENOME-WIDE ASSOCIATION, education, 030304 developmental biology, NATURAL-HISTORY, Arfgengi, medicine.disease, digestive system diseases, immunogenetics, Genetic Loci, Case-Control Studies, Immunology, Genome-Wide Association Study, INFLAMMATORY-BOWEL-DISEASE
Abstract

To access publisher's full text version of this article click on the hyperlink at the bottom of the page Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases. Norwegian PSC Research Center German Ministry of Education and Research through the National Genome Research Network 01GS0809-GP7 Deutsche Forschungsgemeinschaft FR 2821/2-1 Integrated Research and Treatment Center-Transplantation 01EO0802 PopGen Biobank Wellcome Trust 098051 info:eu-repo/grantAgreement/EC/FP7/262055

Published
2013
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11. Structural basis of SUFU-GLI interaction in human Hedgehog signalling regulation

Author

Luca Jovine, Thomas Schwend, C. Finta, A.L. Cherry, Juan Astorga-Wells, M. Karlstrom, Daniele de Sanctis, M. Del Campo, Qianren Jin, R. Toftgard, Angela Criswell, Roman A. Zubarev, Karolinska Inst, Novum, Ctr Biosci, SE-14183 Huddinge, Sweden, Karolinska Inst, Novum, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden, Biomotif AB, SE-18212 Danderyd, Sweden, Karolinska Inst, Dept Med Biochem & Biophys, SE-17177 Stockholm, Sweden, Rigaku Amer Corp, The Woodlands, TX 77381 USA, European Synchrotron Radiation Facility (ESRF), and Cherry, Amy L

Subjects
Models, Molecular, Hedgehog signalling regulation, animal structures, SUFU, Protein Conformation, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Repressor, Biology, Crystallography, X-Ray, Zinc Finger Protein GLI1, 03 medical and health sciences, QH301, 0302 clinical medicine, Protein structure, Structural Biology, Animals, Humans, Amino Acid Sequence, Protein Interaction Maps, Peptide sequence, Transcription factor, 030304 developmental biology, Genetics, 0303 health sciences, Cell growth, General Medicine, Research Papers, Cell biology, Repressor Proteins, Hedgehog signalling, Hedgehogs, 030220 oncology & carcinogenesis, embryonic structures, Signal transduction, Intracellular, Signal Transduction, Transcription Factors, GLI
Abstract

Crystal and small-angle X-ray scattering structures of full-length human SUFU alone and in complex with the conserved SYGHL motif from GLI transcription factors show major conformational changes associated with binding and reveal an intrinsically disordered region crucial for pathway activation., Hedgehog signalling plays a fundamental role in the control of metazoan development, cell proliferation and differentiation, as highlighted by the fact that its deregulation is associated with the development of many human tumours. SUFU is an essential intracellular negative regulator of mammalian Hedgehog signalling and acts by binding and modulating the activity of GLI transcription factors. Despite its central importance, little is known about SUFU regulation and the nature of SUFU–GLI interaction. Here, the crystal and small-angle X-ray scattering structures of full-length human SUFU and its complex with the key SYGHL motif conserved in all GLIs are reported. It is demonstrated that GLI binding is associated with major conformational changes in SUFU, including an intrinsically disordered loop that is also crucial for pathway activation. These findings reveal the structure of the SUFU–GLI interface and suggest a mechanism for an essential regulatory step in Hedgehog signalling, offering possibilities for the development of novel pathway modulators and therapeutics.

Published
2013
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12. Re: A Structured Interdomain Linker Directs Self-Polymerization of Human Uromodulin

Author

Luca Rampoldi, Luca Jovine, K. Nishimura, Martina Brunati, Ling Han, Marcel Bokhove, Daniele de Sanctis, Bokhove, M, Nishimura, K, Brunati, M, Han, L, de Sanctis, D, Rampoldi, L, Jovine, L, Karolinska Inst, Ctr Innovat Med, SE-14183 Huddinge, Sweden, Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden, Ist Sci San Raffaele, Div Genet & Cell Biol, Mol Genet Renal Disorders Unit, I-20132 Milan, Italy, and European Synchrotron Radiation Facility (ESRF)

Subjects
Models, Molecular, 0301 basic medicine, Tamm–Horsfall protein, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Fluorescent Antibody Technique, Crystallography, X-Ray, Madin Darby Canine Kidney Cells, Polymerization, Mice, 0302 clinical medicine, Medicine, Disulfides, TECTA, chemistry.chemical_classification, Extracellular Matrix Proteins, education.field_of_study, Multidisciplinary, biology, Sperm receptor, Biological Sciences, Cell biology, Biochemistry, ZP2, Recombinant Fusion Proteins, Urology, Blotting, Western, Molecular Sequence Data, Mutation, Missense, Computational biology, GPI-Linked Proteins, Maltose-Binding Proteins, 03 medical and health sciences, Dogs, Uromodulin, Animals, Humans, Amino Acid Sequence, education, Gene, X-ray crystallography, Innate immune system, zona pellucida domain, business.industry, Protein Structure, Tertiary, HEK293 Cells, 030104 developmental biology, chemistry, Structural Homology, Protein, biology.protein, Protein Multimerization, Glycoprotein, business, Sequence Alignment, Linker, 030217 neurology & neurosurgery, Function (biology)
Abstract

International audience; Uromodulin (UMOD)/Tamm-Horsfall protein, the most abundant human urinary protein, plays a key role in chronic kidney diseases and is a promising therapeutic target for hypertension. Via its bipartite zona pellucida module (ZP-N/ZP-C), UMOD forms extracellular filaments that regulate kidney electrolyte balance and innate immunity, as well as protect against renal stones. Moreover, salt-dependent aggregation of UMOD filaments in the urine generates a soluble molecular net that captures uropathogenic bacteria and facilitates their clearance. Despite the functional importance of its homopolymers, no structural information is available on UMOD and how it self-assembles into filaments. Here, we report the crystal structures of polymerization regions of human UMOD and mouse ZP2, an essential sperm receptor protein that is structurally related to UMOD but forms heteropolymers. The structure of UMOD reveals that an extensive hydrophobic interface mediates ZP-N domain homodimerization. This arrangement is required for filament formation and is directed by an ordered ZP-N/ZP-C linker that is not observed in ZP2 but is conserved in the sequence of deafness/Crohn's disease-associated homopolymeric glycoproteins a-tectorin (TECTA) and glycoprotein 2 (GP2). Our data provide an example of how interdomain linker plasticity can modulate the function of structurally similar multidomain proteins. Moreover, the architecture of UMOD rationalizes numerous pathogenic mutations in both UMOD and TECTA genes

Published
2016
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13. Brain charts for the human lifespan

Author

Armin Raznahan, Eric Courchesne, Andrea Parolin Jackowski, Kamen A. Tsvetanov, Cameron T. Ellis, R.C. Gur, Bin Bae J, Park Mtm, Pedro A. Valdes-Sosa, Simon N. Vandekar, Jacob W. Vogel, Juan Zhou, Machteld Marcelis, Kiho Im, Patricia Ellen Grant, Minhui Ouyang, Blesa Cabez M, Michael V. Lombardo, Sarah E. Morgan, James P. Boardman, Adamson C, Calhoun Vd, Delarue M, James H. Cole, Pichet Binette A, Roberto Toro, David H. Rowitch, Nynke A. Groenewold, Kevin M. Anderson, David T.W. Jones, Michael Schöll, Wang Ys, Aiden Corvin, R.E. Gur, Damien A. Fair, Gareth Ball, Herma Lina Schaare, Andrew Zalesky, Evdokia Anagnostou, Michael J. Meaney, Taki Y, Gareth J. Sullivan, Warrier, Petra E. Vértes, Chixiang Chen, Lisa T. Eyler, Wei Liao, Tomáš Paus, Jeremy A. Elman, Phillip McGuire, Hisham Ziauddeen, William S. Kremen, Etienne Vachon-Presseau, E.T. Bullmore, Christophe Tzourio, White, Hammill Cf, Mothersill D, Richard N. Henson, Jiang Qiu, Duncan E. Astle, Fabrice Crivello, Paul C. Fletcher, Chertavian C, Kim K, Jennifer Crosbie, Russell Schachar, Gabriel A. Devenyi, Manfred G. Kitzbichler, Tianye Jia, Trey Hedden, Sang Jae Lee, Ross D. Markello, Silke Kern, Ian M. Goodyer, Keith A. Johnson, Frauke Beyer, Bernard Mazoyer, A. Heinz, Sylvane Desrivières, Rosenberg, Gary Donohoe, Ong Mq, Alexander D. Edwards, Dan J. Stein, Nenad Medic, Zuo Xn, Travis T. Mallard, Peter Fonagy, Lindsay W. Victoria, Ingmar Skoog, Avram J. Holmes, Jason P. Lerch, Jed T. Elison, Jianfu Li, John H. Gilmore, Rosemary Holt, Caitlin K. Rollins, Carol E. Franz, Pedro Mario Pan, Saashi A Bedford, Yang N, Jonathan C Ipser, Richard A. I. Bethlehem, Tuulari Jj, Stolicyn A, Hua Huang, Bratislav Misic, Conor Liston, Ayub M, Lisa Ronan, Yeo Bt, Sophie Adler, Charles J. Lynch, Faith M. Gunning, Konrad Wagstyl, M. Mallar Chakravarty, John Suckling, Theodore D. Satterthwaite, Bharath Holla, Yap Seng Chong, Jinglei Lv, Jakob Seidlitz, Niall J Bourke, Xinlei Qian, Simon Baron-Cohen, Cynthia M. Ortinau, Deirel Paz Linares, Thyreau B, René S. Kahn, Aaron P. Schultz, Vanessa Cropley, Eric Westman, Mitchell Valdés-Sosa, Rik Ossenkoppele, André Zugman, Hasse Karlsson, Sylvia Villeneuve, Katja Heuer, Di Biase Ma, Margaret L. Westwater, Sofie L. Valk, David J. Sharp, Brigitte Landeau, Matthew Borzage, Kirsten A. Donald, Timothy Rittman, Richard Beare, Giovanni Abrahão Salum, Gunter Schumann, Ryuta Kawashima, Romero-Garcia R, John Blangero, Yun Hj, Russel T. Shinohara, Nicolas Crossley, Simon K. Warfield, Karen Pierce, George S. Alexopoulos, Katharine Dunlop, David C. Glahn, Francois Lalonde, Anqi Qiu, Lana Vasung, Gaël Chételat, Lídice Galán-García, Clifford R. Jack, Reisa A. Sperling, Anna Zettergren, Elizabeth Kelley, Arno Villringer, Andrea Mechelli, Benegal, Aaron Alexander-Bloch, Nicholas B. Turk-Browne, van Amelsvoort T, John D. Lewis, Heather C. Whalley, A. V. Witte, Zdenka Pausova, Joel T. Nigg, Heather J. Zar, Raymond J. Dolan, Christopher D. Smyser, Jay N. Giedd, Lena Palaniyappan, Ali Gholipour, Areces-Gonzalez A, Peter B. Jones, Jacqueline Hoare, Oskar Hansson, Linnea Karlsson, C Pantelis, Paly L, Bonnie Auyeung, Jorge Bosch-Bayard, Bethlehem, Richard [0000-0002-0714-0685], White, Simon [0000-0001-8642-7037], Astle, Duncan [0000-0002-7042-5392], Baron-Cohen, Simon [0000-0001-9217-2544], Henson, Rik [0000-0002-0712-2639], Jones, Peter [0000-0002-0387-880X], Kitzbichler, Manfred [0000-0002-4494-0753], Rittman, Timothy [0000-0003-1063-6937], Rowitch, David [0000-0002-0079-0060], Tsvetanov, Kamen A. [0000-0002-3178-6363], Westwater-Wozniak, Margaret [0000-0002-2918-0979], Ziauddeen, Hisham [0000-0003-4044-1719], Apollo - University of Cambridge Repository, British Academy, Autism Research Trust, National Institute of Mental Health (US), UK Research and Innovation, Medical Research Council (UK), National Institute for Health and Care Research (US), Wellcome Trust, University of Cambridge, Cambridge Biomedical Research Centre, University of Cambridge [UK] (CAM), University of Pennsylvania, Yale University [New Haven], Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et imagerie des troubles neurologiques (PhIND), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Child and Adolescent Psychiatry Department [AP- HP Hôpital Robert Debré], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de Neuroscience - Department of Neuroscience, Centre de Recherche Interdisciplinaire / Center for Research and Interdisciplinarity [Paris, France] (CRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, MUMC+: MA Med Staf Spec Psychiatrie (9), Neurology, Amsterdam Neuroscience - Neurodegeneration, 3R-BRAIN, AIBL, Alzheimer’s Disease Neuroimaging Initiative, Alzheimer’s Disease Repository Without Borders Investigators, CALM Team, Cam-CAN, CCNP, COBRE, cVEDA, ENIGMA Developmental Brain Age Working Group, Developing Human Connectome Project, FinnBrain, Harvard Aging Brain Study, IMAGEN, KNE96, The Mayo Clinic Study of Aging, NSPN, POND, The PREVENT-AD Research Group, VETSA, [Bethlehem, R. A. I.] Univ Cambridge, Dept Psychiat, Autism Res Ctr, Cambridge, England, [Auyeung, B.] Univ Cambridge, Dept Psychiat, Autism Res Ctr, Cambridge, England, [Baron-Cohen, S.] Univ Cambridge, Dept Psychiat, Autism Res Ctr, Cambridge, England, [Bedford, S. A.] Univ Cambridge, Dept Psychiat, Autism Res Ctr, Cambridge, England, [Holt, R.] Univ Cambridge, Dept Psychiat, Autism Res Ctr, Cambridge, England, [Lombardo, M. V.] Univ Cambridge, Dept Psychiat, Autism Res Ctr, Cambridge, England, [Bethlehem, R. A. I.] Univ Cambridge, Dept Psychiat, Brain Mapping Unit, Cambridge, England, [Kitzbichler, M. G.] Univ Cambridge, Dept Psychiat, Brain Mapping Unit, Cambridge, England, [Seidlitz, J.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA, [Vogel, J. W.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA, [Gur, R. E.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA, [Gur, R. C.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA, [Jackowski, A. P.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA, [Satterthwaite, T. D.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA, [Alexander-Bloch, A. F.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA, [Seidlitz, J.] Childrens Hosp Philadelphia, Dept Child & Adolescent Psychiat & Behav Sci, Philadelphia, PA 19104 USA, [Alexander-Bloch, A. F.] Childrens Hosp Philadelphia, Dept Child & Adolescent Psychiat & Behav Sci, Philadelphia, PA 19104 USA, [Seidlitz, J.] Childrens Hosp Philadelphia & Penn Med, Lifespan Brain Inst, Philadelphia, PA USA, [Chertavian, C.] Childrens Hosp Philadelphia & Penn Med, Lifespan Brain Inst, Philadelphia, PA USA, [Gur, R. E.] Childrens Hosp Philadelphia & Penn Med, Lifespan Brain Inst, Philadelphia, PA USA, [Gur, R. C.] Childrens Hosp Philadelphia & Penn Med, Lifespan Brain Inst, Philadelphia, PA USA, [Alexander-Bloch, A. F.] Childrens Hosp Philadelphia & Penn Med, Lifespan Brain Inst, Philadelphia, PA USA, [White, S. R.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Goodyer, I. M.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Henson, R. N.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Jones, P. B.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Kitzbichler, M. G.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Medic, N.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Morgan, S. E.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Romero-Garcia, R.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Ronan, L.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Suckling, J.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Vertes, P. E.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Warrier, V.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Westwater, M. L.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Ziauddeen, H.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Bullmore, E. T.] Univ Cambridge, Dept Psychiat, Cambridge, England, [White, S. R.] Univ Cambridge, MRC Biostat Unit, Cambridge, England, [Vogel, J. W.] Univ Penn, Lifespan Informat & Neuroimaging Ctr, Philadelphia, PA 19104 USA, [Satterthwaite, T. D.] Univ Penn, Lifespan Informat & Neuroimaging Ctr, Philadelphia, PA 19104 USA, [Anderson, K. M.] Yale Univ, Dept Psychol, New Haven, CT USA, [Ellis, C. T.] Yale Univ, Dept Psychol, New Haven, CT USA, [Turk-Browne, N. B.] Yale Univ, Dept Psychol, New Haven, CT USA, [Adamson, C.] Murdoch Childrens Res Inst, Dev Imaging, Melbourne, Vic, Australia, [Ball, G.] Murdoch Childrens Res Inst, Dev Imaging, Melbourne, Vic, Australia, [Beare, R.] Murdoch Childrens Res Inst, Dev Imaging, Melbourne, Vic, Australia, [Jackowski, A. P.] Murdoch Childrens Res Inst, Dev Imaging, Melbourne, Vic, Australia, [Adamson, C.] Monash Univ, Dept Med, Melbourne, Vic, Australia, [Beare, R.] Monash Univ, Dept Med, Melbourne, Vic, Australia, [Adler, S.] UCL Great Ormond St Inst Child Hlth, London, England, [Alexopoulos, G. S.] Weill Cornell Med, Dept Psychiat, Weill Cornell Inst Geriatr Psychiat, New York, NY USA, [Anagnostou, E.] Univ Toronto, Dept Pediat, Toronto, ON, Canada, [Anagnostou, E.] Holland Bloorview Kids Rehabil Hosp, Toronto, ON, Canada, [Pierce, K.] Holland Bloorview Kids Rehabil Hosp, Toronto, ON, Canada, [Areces-Gonzalez, A.] Univ Elect Sci & Technol China, MOE Key Lab NeuroInformat, Clin Hosp, Chengdu Brain Sci Inst, Chengdu, Peoples R China, [Paz-Linares, D.] Univ Elect Sci & Technol China, MOE Key Lab NeuroInformat, Clin Hosp, Chengdu Brain Sci Inst, Chengdu, Peoples R China, [Areces-Gonzalez, A.] Univ Pinar del Rio Hermanos Saiz Montes de Oca, Pinar Del Rio, Cuba, [Astle, D. E.] Univ Cambridge, MRC Cognit & Brain Sci Unit, Cambridge, England, [Henson, R. N.] Univ Cambridge, MRC Cognit & Brain Sci Unit, Cambridge, England, [Whalley, H. C.] Univ Cambridge, MRC Cognit & Brain Sci Unit, Cambridge, England, [Auyeung, B.] Univ Edinburgh, Sch Philosophy Psychol & Language Sci, Dept Psychol, Edinburgh, Midlothian, Scotland, [Pausova, Z.] Univ Edinburgh, Sch Philosophy Psychol & Language Sci, Dept Psychol, Edinburgh, Midlothian, Scotland, [Ayub, M.] Queens Univ, Dept Psychiat, Ctr Neurosci Studies, Kingston, ON, Canada, [Ayub, M.] UCL, Mental Hlth Neurosci Res Dept, Div Psychiat, London, England, [Bae, J.] Seoul Natl Univ, Bundang Hosp, Dept Neuropsychiat, Seongnam, South Korea, [Ball, G.] Univ Melbourne, Dept Paediat, Melbourne, Vic, Australia, [Baron-Cohen, S.] Cambridgeshire & Peterborough NHS Fdn Trust, Cambridge Lifetime Asperger Syndrome Serv CLASS, Cambridge, England, [Benegal, V.] Natl Inst Mental Hlth & Neurosci NIMHANS, Ctr Addict Med, Bengaluru, India, [Beyer, F.] Max Planck Inst Human Cognit & Brain Sci, Dept Neurol, Leipzig, Germany, [Villringer, A.] Max Planck Inst Human Cognit & Brain Sci, Dept Neurol, Leipzig, Germany, [Witte, A. V.] Max Planck Inst Human Cognit & Brain Sci, Dept Neurol, Leipzig, Germany, [Blangero, J.] Univ Texas Rio Grande Valley, South Texas Diabet & Obes Inst, Dept Human Genet, Edinburg, TX USA, [Blesa Cabez, M.] Univ Edinburgh, MRC Ctr Reprod Hlth, Edinburgh, Midlothian, Scotland, [Boardman, J. P.] Univ Edinburgh, MRC Ctr Reprod Hlth, Edinburgh, Midlothian, Scotland, [Sullivan, G.] Univ Edinburgh, MRC Ctr Reprod Hlth, Edinburgh, Midlothian, Scotland, [Borzage, M.] Univ Southern Calif, Childrens Hosp Los Angeles, Keck Sch Med, Fetal & Neonatal Inst,Div Neonatol,Dept Pediat, Los Angeles, CA 90007 USA, [Bosch-Bayard, J. F.] Montreal Neurol Inst, Ludmer Ctr Neuroinformat & Mental Hlth, McGill Ctr Integrat Neurosci, Montreal, PQ, Canada, [Bosch-Bayard, J. F.] McGill Univ, Montreal, PQ, Canada, [Chakravarty, M. 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E.] Alan Turing Inst, London, England, [Mothersill, D.] Natl Coll Ireland, Sch Business, Dept Psychol, Dublin, Ireland, [Mothersill, D.] Natl Univ Ireland Galway, Sch Psychol, Galway, Ireland, [Mothersill, D.] Natl Univ Ireland Galway, Ctr Neuroimaging & Cognit Genom, Galway, Ireland, [Mothersill, D.] Trinity Coll Dublin, Dept Psychiat, Dublin, Ireland, [Nigg, J.] Oregon Hlth & Sci Univ, Dept Psychiat, Sch Med, Portland, OR 97201 USA, [Ong, M. Q. W.] Natl Univ Singapore, Yong Loo Lin Sch Med, Ctr Sleep & Cognit, Singapore, Singapore, [Qian, X.] Natl Univ Singapore, Yong Loo Lin Sch Med, Ctr Sleep & Cognit, Singapore, Singapore, [Zhou, J. 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M.] Natl Inst Dev Psychiat Children & Adolescents INP, Sao Poalo, Brazil, [Zugman, A.] Natl Inst Dev Psychiat Children & Adolescents INP, Sao Poalo, Brazil, [Pantelis, C.] Univ Melbourne, Dept Psychiat, Melbourne Neuropsychiat Ctr, Carlton, Vic, Australia, [Pantelis, C.] Melbourne Hlth, Carlton, Vic, Australia, [Pantelis, C.] Univ Melbourne, Melbourne Sch Engn, Parkville, Vic, Australia, [Pantelis, C.] Florey Inst Neurosci & Mental Hlth, Parkville, Vic, Australia, [Park, M. M.] Western Univ, Schulich Sch Med & Dent, Dept Psychiat, London, ON, Canada, [Rollins, C. K.] Univ Montreal, Dept Psychiat, Fac Med, Montreal, PQ, Canada, [Rollins, C. K.] Univ Montreal, CHU St Justine, Montreal, PQ, Canada, [Romero-Garcia, R.] Univ Toronto, Dept Psychiat, Toronto, ON, Canada, [Romero-Garcia, R.] Univ Toronto, Dept Psychol, Toronto, ON, Canada, [Rosenberg, M. D.] Univ Toronto, Dept Physiol, Toronto, ON, Canada, [Rosenberg, M. 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P.] Massachusetts Gen Hosp, Dept Radiol, Athinoula Martinos Ctr Biomed Imaging, Charlestown, MA USA, [Schumann, G.] Fudan Univ, Inst Sci & Technol Brain Inspired Intelligence, Ctr Populat Neurosci & Stratified Med PONS, Shanghai, Peoples R China, [Schumann, G.] Charite Campus Mitte, Dept Psychiat & Psychotherapy, Charite Mental Hlth, PONS Ctr, Berlin, Germany, [Scholl, M.] Univ Gothenburg, Wallenberg Ctr Mol & Translat Med, Gothenburg, Sweden, [Scholl, M.] Univ Gothenburg, Dept Psychiat & Neurochem, Gothenburg, Sweden, [Scholl, M.] UCL, Queens Sq Inst Neurol, Dementia Res Ctr, London, England, [Sharp, D.] UK Dementia Res Inst, Care Res & Technol Ctr, London, England, [Shinohara, R. T.] Univ Penn, Perelman Sch Med, Dept Radiol, Ctr Biomed Image Comp & Analyt, Philadelphia, PA 19104 USA, [Smyser, C. D.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA, [Smyser, C. D.] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA, [Smyser, C. D.] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA, [Stein, D. J.] Univ Cape Town, Dept Psychiat, SA MRC Unit Risk & Resilience Mental Disorders, Cape Town, South Africa, [Stein, D. J.] Univ Cape Town, Neurosci Inst, Cape Town, South Africa, [Stolicyn, A.] Univ Edinburgh, Ctr Clin Brain Sci, Div Psychiat, Edinburgh, Midlothian, Scotland, [Whalley, H. C.] Univ Edinburgh, Ctr Clin Brain Sci, Div Psychiat, Edinburgh, Midlothian, Scotland, [Toro, R.] Inst Pasteur, Dept Neurosci, Paris, France, [Traut, N.] Inst Pasteur, Dept Neurosci, Paris, France, [Traut, N.] Univ Paris 05, Ctr Res & Interdisciplinar CRI, Paris, France, [Tsvetanov, K. A.] Univ Cambridge, Dept Psychol, Cambridge, England, [Turk-Browne, N. B.] Yale Univ, Wu Tsai Inst, New Haven, CT USA, [Tuulari, J. J.] Univ Turku, Dept Clin Med, Turku, Finland, [Tuulari, J. J.] Univ Turku, Turku Coll Sci Med & Technol, Turku, Finland, [Tzourio, C.] Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, CHU Bordeaux, U1219,INSERM, Bordeaux, France, [Vachon-Presseau, E.] McGill Univ, Fac Dent Med & Oral Hlth Sci, Montreal, PQ, Canada, [Valdes-Sosa, P. A.] McGill Univ, Alan Edwards Ctr Res Pain AECRP, Montreal, PQ, Canada, [Valk, S. L.] Forschungszentrum Julich, Inst Neurosci & Med 7, Julich, Germany, [Valk, S. L.] Max Planck Inst Human Cognit & Brain Sci, Leipzig, Germany, [van Amelsvoort, T.] Maastricht Univ, Dept Psychiat & Neurosychol, Maastricht, Netherlands, [Vandekar, S. N.] Vanderbilt Univ, Dept Biostat, 221 Kirkland Hall, Nashville, TN 37235 USA, [Villeneuve, S.] Vanderbilt Univ, Med Ctr, Dept Biostat, Nashville, TN USA, [Villringer, A.] Univ Leipzig, Clin Cognit Neurol, Med Ctr, Leipzig, Germany, [Witte, A. V.] Univ Leipzig, Clin Cognit Neurol, Med Ctr, Leipzig, Germany, [Zuo, X. N.] Univ Leipzig, Clin Cognit Neurol, Med Ctr, Leipzig, Germany, [Wang, Y. S.] Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing, Peoples R China, [Yang, N.] Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing, Peoples R China, [Yeo, B.] Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing, Peoples R China, [Zuo, X. N.] Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing, Peoples R China, [Wang, Y. S.] Beijing Normal Univ, IDG McGovern Inst Brain Res, Dev Populat Neuroscience Res Ctr, Beijing, Peoples R China, [Yang, N.] Beijing Normal Univ, IDG McGovern Inst Brain Res, Dev Populat Neuroscience Res Ctr, Beijing, Peoples R China, [Zuo, X. N.] Beijing Normal Univ, IDG McGovern Inst Brain Res, Dev Populat Neuroscience Res Ctr, Beijing, Peoples R China, [Wang, Y. S.] Natl Basic Sci Data Ctr, Beijing, Peoples R China, [Yang, N.] Natl Basic Sci Data Ctr, Beijing, Peoples R China, [Zuo, X. N.] Natl Basic Sci Data Ctr, Beijing, Peoples R China, [Wang, Y. S.] Chinese Acad Sci, Res Ctr Lifespan Dev Brain & Mind, Inst Psychol, Beijing, Peoples R China, [Yang, N.] Chinese Acad Sci, Res Ctr Lifespan Dev Brain & Mind, Inst Psychol, Beijing, Peoples R China, [Westman, E.] Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, Stockholm, Sweden, [Witte, A. V.] Univ Leipzig, CRC 1052 Obes Mech, Fac Med, Leipzig, Germany, [Zhou, J. H.] Natl Univ Singapore, Dept Elect & Comp Engn, Singapore, Singapore, [Yeo, B.] Natl Univ Singapore, Yong Loo Lin Sch Med, Ctr Sleep & Cognit, Singapore, Singapore, [Yeo, B.] Natl Univ Singapore, Yong Loo Lin Sch Med, Ctr Translat MR Res, Singapore, Singapore, [Yeo, B.] Natl Univ Singapore, N1 Inst Hlth, Singapore, Singapore, [Yeo, B.] Natl Univ Singapore, Inst Digital Med, Singapore, Singapore, [Yun, H.] Natl Univ Singapore, Integrat Sci & Engn Programme ISEP, Singapore, Singapore, [Zar, H. J.] Univ Melbourne, Dept Biomed Engn, Melbourne, Vic, Australia, [Zhou, J. H.] Natl Univ Singapore, Yong Loo Lin Sch Med, Ctr Translat Magnet Resonance Res, Singapore, Singapore, [Ziauddeen, H.] Univ Cambridge, Wellcome Trust MRC Inst Metab Sci, Cambridge, England, [Zugman, A.] NIMH, NIH, Bethesda, MD 20892 USA, [Zugman, A.] Escola Paulista Med, Dept Psychiat, Sao Paulo, Brazil, [Zuo, X. N.] Nanning Normal Univ, Sch Educ Sci, Key Lab Brain & Educ, Nanning, Peoples R China, British Academy Postdoctoral fellowship, NIMH, UKRI Medical Research Council, NIHR Cambridge Biomedical Research Centre, NIHR Senior Investigator award, MRC research infrastructure award, Commonwealth Scientific and Industrial Research Organisation (CSIRO), and Ontario Brain Institute

Subjects
631/378/2649, OpenPain Project, KNE96, Growth, Psychiatric-disorders, DISEASE, 3R-BRAIN, Brain charts, MRI Brain, OASIS-3, Disease, CCNP, 631/378/2571, UMN BCP, Multidisciplinary, medicine.diagnostic_test, PSYCHIATRIC-DISORDERS, article, Brain, Human brain, ASSOCIATION, Magnetic Resonance Imaging, Harvard Aging Brain Study, The Mayo Clinic Study of Aging, NSPN, medicine.anatomical_structure, GROWTH, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], ddc:500, BURDEN, WHITE-MATTER, FinnBrain, Harvard Aging Brain Study, Organization, Mri, MRI, medicine.medical_specialty, Concurrent validity, MODELS, Cam-CAN, Longevity, CALM Team, POND, Neuroimaging, Burden, ORGANIZATION, AIBL, The PREVENT-AD Research Group, VETSA, Cortical thickness, Association, Physical medicine and rehabilitation, FinnBrain, IMAGEN, KNE96, White-matter, medicine, Humans, ASRB, 631/378/1689, COBRE, business.industry, 631/378/2611, Brain morphometry, Neurosciences, Alzheimer’s Disease Repository Without Borders Investigators, Magnetic resonance imaging, Alzheimer’s Disease Neuroimaging Initiative, Anthropometry, Body Height, Brain growth, Birth, 59/57, Normative, IMAGEN, ENIGMA Developmental Brain Age working group, NSPN, business, CCNP, 3R-BRAIN, CORTICAL THICKNESS, Developing Human Connectome Project, ENIGMA Developmental Brain Age working group, The PREVENT-AD Research Group, VETSA, Bullmore, E.T
Abstract

Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes., R.A.I.B. was supported by a British Academy Postdoctoral fellowship and by the Autism Research Trust. J. Seidlitz was supported by NIMH T32MH019112-29 and K08MH120564. S.R.W. was funded by UKRI Medical Research Council MC_UU_00002/2 and was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). E.T.B. was supported by an NIHR Senior Investigator award and the Wellcome Trust collaborative award for the Neuroscience in Psychiatry Network. A.F.A.-B. was supported by NIMH K08MH120564. Data were curated and analysed using a computational facility funded by an MRC research infrastructure award (MR/M009041/1) to the School of Clinical Medicine, University of Cambridge and supported by the mental health theme of the NIHR Cambridge Biomedical Research Centre.

Published
2022
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14. Evaluation of 10 Cone-beam Computed Tomographic Devices for Endodontic Assessment of Fine Anatomic Structures

Author

Karla de Faria Vasconcelos, Mário Tanomaru-Filho, Victor Aquino Wanderley, Mansour Nadjmi, Matheus Lima Oliveira, Reinhilde Jacobs, Ruben Pauwels, Jader Camilo Pinto, André Ferreira Leite, Universidade Estadual Paulista (Unesp), Katholieke Univ Leuven, Univ Hosp Leuven, Universidade Estadual de Campinas (UNICAMP), Universidade de Brasília (UnB), Aarhus Univ, and Karolinska Inst

Subjects
0301 basic medicine, Scanner, Cone beam computed tomography, medicine.medical_specialty, cone-beam computed tomography, Image quality, Computer science, Fleiss' kappa, artifacts, Computed tomographic, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, General Dentistry, Tooth, Nonvital, Orthodontics, Phantoms, Imaging, X-Ray Microtomography, 030206 dentistry, Cone-Beam Computed Tomography, Endodontics, endodontics, 030104 developmental biology, Endodontically treated tooth, Apical delta, Anatomy
Abstract

Made available in DSpace on 2021-06-25T15:06:17Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-06-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Fundacao de Apoio a Pesquisa do Distrito Federal European Union Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie grant Aarhus University Research Foundation (AIAS-COFUND) Introduction: The purpose of this study was to classify 10 cone-beam computed tomographic (CBCT) devices using a ranking model according to the detection of fine endodontic structures. Methods: A dedicated dentate anthropomorphic phantom was scanned 2 times using 10 CBCT devices without any metal (metal-free condition) and with an endodontically treated tooth containing a metallic post (metal condition). A reference image acquired on an industrial micro-CT scanner was used to register all CBCT images, yielding corresponding anatomic slices. Afterward, 3 experienced observers assessed all acquired CBCT images for their ability to assess a narrow canal, isthmus, and apical delta ramification using a categoric rank from 1 (best) to 10 (worst). Fleiss kappa statistics were used to calculate intra-and interobserver agreements for each CBCT device separately. Based on the observers' scores, general linear mixed models were applied to compare image quality among different CBCT devices for performing endodontic diagnostic tasks (a 5 .05). Results: The 10 CBCT devices performed differently for the evaluated endodontic tasks (P , .05), with 3 devices performing better for endodontic feature detection. Yet, in the presence of metal, only 2 devices were able to keep a high level of endodontic feature detection. Conclusions: The evaluated endodontic tasks were CBCT device dependent, and their detection was influenced by the presence of metal. (J Endod 2021;47:947-953.) Sao Paulo State Univ, Sch Dent, Dept Restorat Dent, Araraquara, SP, Brazil Katholieke Univ Leuven, OMFS IMPATH Res Grp, Dept Imaging & Pathol, Fac Med, Leuven, Belgium Univ Hosp Leuven, Oral & Maxillofacial Surg, Leuven, Belgium Univ Estadual Campinas, Piracicaba Dent Sch, Div Oral Radiol, Dept Oral Diag, Piracicaba, SP, Brazil Univ Brasilia, Dept Dent, Fac Hlth Sci, Brasilia, DF, Brazil Aarhus Univ, Aarhus Inst Adv Studies, Aarhus, Denmark Katholieke Univ Leuven, Dept Mech Engn, Leuven, Belgium Karolinska Inst, Dept Dent Med, Stockholm, Sweden Sao Paulo State Univ, Sch Dent, Dept Restorat Dent, Araraquara, SP, Brazil CAPES: 001 FAPESP: 2019/22885-0 Fundacao de Apoio a Pesquisa do Distrito Federal: 23106.013588/2019-5 European Union Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie grant: 754513

Published
2021
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15. Effects of vitamin D-induced supernatant of placental explants from preeclamptic women on oxidative stress and nitric oxide bioavailability in human umbilical vein endothelial cells

Author

Priscila Rezeck Nunes, Virginia Juliani Gomes, Maria Terezinha Serrão Peraçoli, Mattias Carlström, Valeria C. Sandrim, José Carlos Peraçoli, Universidade Estadual Paulista (Unesp), and Karolinska Inst

Subjects
0301 basic medicine, Medicine (General), Physiology, QH301-705.5, Placenta, Immunology, Biophysics, Biological Availability, Ocean Engineering, medicine.disease_cause, Nitric Oxide, Biochemistry, Umbilical vein, Nitric oxide, Preeclampsia, Andrology, Lipid peroxidation, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, R5-920, Pre-Eclampsia, Pregnancy, medicine, Human Umbilical Vein Endothelial Cells, Humans, General Pharmacology, Toxicology and Pharmaceutics, Vitamin D, Biology (General), Cells, Cultured, General Neuroscience, Cell Biology, General Medicine, Hydrogen Peroxide, medicine.disease, Malondialdehyde, Bioavailability, 030104 developmental biology, chemistry, Oxidative stress, Placental explants, 030220 oncology & carcinogenesis, Female, Explant culture, Research Article
Abstract

Made available in DSpace on 2021-06-25T15:06:18Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-01-01. Added 1 bitstream(s) on 2021-07-15T14:36:46Z : No. of bitstreams: 1 S0100-879X2021000800604.pdf: 632798 bytes, checksum: 7a3373bbfe0a871d577a001fd4fb9313 (MD5) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Swedish Research Council Swedish Heart and Lung Foundation NovoNordisk The study evaluated the effect of the supernatant of placental explants from preeclamptic (PE) and normotensive (NT) pregnant women after tissue treatment with or without vitamin D (VD) on oxidative stress and nitric oxide (NO) bioavailability in human umbilical vein endothelial cells (HUVEC). Placental explants were prepared from eight NT and eight PE women, and supernatants were obtained after incubation with or without hydrogen peroxide (H2O2) and/or VD. HUVEC were cultured for 24 h with supernatants, and the following parameters were analyzed in HUVEC cultures: NO, nitrate (NO3-), and nitrite (NO2-) levels, lipid peroxidation, and intracellular reactive oxygen species (ROS). Results showed that the production of NO3-, NO2-, malondialdehyde (MDA), and ROS were significantly higher in HUVEC treated with explant supernatant from PE compared to NT pregnant women, while the supernatant of PE explants treated with VD led to a decrease in these parameters. A significantly high production of NO was detected in HUVEC cultured with control supernatant of NT group, and in cultures treated with supernatant of PE explants treated with VD. Taken together, these results demonstrated that cultures of placental explants from PE women with VD treatment generated a supernatant that decreased oxidative stress and increased the bioavailability of NO in endothelial cells. Univ Estadual Paulista, Fac Med Botucatu, Dept Ginecol & Obstet, Botucatu, SP, Brazil Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden Univ Estadual Paulista, Inst Biociencias, Dept Biofis & Farmacol, Botucatu, SP, Brazil Univ Estadual Paulista, Fac Med Botucatu, Dept Ginecol & Obstet, Botucatu, SP, Brazil Univ Estadual Paulista, Inst Biociencias, Dept Biofis & Farmacol, Botucatu, SP, Brazil FAPESP: 2016/23452-2 FAPESP: 2019/00234-8 Swedish Research Council: 2016-01381 Swedish Research Council: 2020-01645 Swedish Heart and Lung Foundation: 20170124 Swedish Heart and Lung Foundation: 20180568 NovoNordisk: 0055026

Published
2021

16. Different profiles of circulating arginase 2 in subtypes of preeclampsia pregnant women

Author

Mariana Bertozzi-Matheus, Ricardo de Carvalho Cavalli, Sarah Viana-Mattioli, Thaina Omia Bueno-Pereira, Mattias Carlström, Valeria C. Sandrim, Universidade Estadual Paulista (Unesp), Karolinska Inst, and Universidade de São Paulo (USP)

Subjects
Adult, 030213 general clinical medicine, medicine.medical_specialty, Clinical Biochemistry, Disease, 030204 cardiovascular system & hematology, Arginine, Nitric Oxide, Nitric oxide, Preeclampsia, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, FÁRMACOS (SISTEMA CARDIOVASCULAR), 0302 clinical medicine, Pre-Eclampsia, Pregnancy, Internal medicine, Humans, Medicine, No production, Antihypertensive Agents, Fetus, Arginase, business.industry, General Medicine, Middle Aged, medicine.disease, Blood pressure, Endocrinology, chemistry, antihypertensive drugs, Gestation, Female, business
Abstract

Made available in DSpace on 2021-06-25T15:05:50Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-06-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Background and aims: Preeclampsia (PE) is a gestational hypertensive disease responsible for high maternal and fetal morbidity and mortality. The increase in blood pressure is associated with a decrease in the bioavailability of nitric oxide (NO). Arginase interferes with NO production consuming L-arginine, a substrate required by endothelial NO synthase to NO formation. No previous study has quantified the circulating levels of the two arginase isoforms (arginase 1 and arginase 2) in the plasma of pregnant women with PE. Therefore, our objective is to evaluate these plasma levels in healthy pregnant women and PE with or without severe features and who respond or not to antihypertensive therapy. Methods: We compared 29 healthy pregnant women with 56 pregnant women with PE, who were also divided into with severe features (n = 24) or without severe features (n = 32) and into responsive (n = 29) or nonresponsive to antihypertensive therapy (n = 27). We quantified the plasmatic expression of arginase 1 and arginase 2 by ELISA kits. Results: While similar levels of arginase 1 were found among groups, lower arginase 2 plasma levels were found in PE without severe features and responsive to antihypertensive drugs when compared to healthy pregnant women. There was no difference between arginase 2 levels in PE with severe features and nonresponsive group when compared to healthy pregnant women. Conclusion: This shows different circulation profiles of arginase 2 among groups, suggesting the existence of mechanisms of arginase 2 modulation in pregnant women with PE associated with the severity of the disease and responsiveness to antihypertensive treatment. Univ Estadual Paulista, Inst Biosci Botucatu, Dept Biophys & Pharmacol, BR-18680000 Botucatu, SP, Brazil Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Gynecol & Obstet, BR-14049900 Sao Paulo, Brazil Univ Estadual Paulista, Inst Biosci Botucatu, Dept Biophys & Pharmacol, BR-18680000 Botucatu, SP, Brazil FAPESP: 2019/072308 FAPESP: 2019/266425 FAPESP: 2019/266402

Published
2021
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17. Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants

Author

Zhou, B, Carrillo-Larco, Rm, Danaei, G, Riley, Lm, Paciorek, Cj, Stevens, Ga, Gregg, Ew, Bennett, Je, Solomon, B, Singleton, Rk, Sophiea, Mk, Iurilli, Mlc, Lhoste, Vpf, Cowan, Mj, Savin, S, Woodward, M, Balanova, Y, Cifkova, R, Damasceno, A, Elliott, P, Farzadfar, F, He, J, Ikeda, N, Kengne, Ap, Khang, Yh, Kim, Hc, Laxmaiah, A, Lin, Hh, Maira, Pm, Miranda, Jj, Neuhauser, H, Sundstrom, J, Varghese, C, Widyahening, Is, Zdrojewski, T, Ezzati, M, Abarca-Gomez, L, Abdeen, Za, Rahim, Hfa, Abu-Rmeileh, Nm, Acosta-Cazares, B, Adams, Rj, Aekplakorn, W, Afsana, K, Afzal, S, Agdeppa, Ia, Aghazadeh-Attari, J, Aguilar-Salinas, Ca, Agyemang, C, Ahmad, Na, Ahmadi, A, Ahmadi, N, Ahmadizar, F, Ahmed, Sh, Ahrens, W, Ajlouni, K, Al-Raddadi, R, Alarouj, M, Albuhairan, F, Aldhukair, S, Ali, Mm, Alkandari, A, Alkerwi, A, Allin, K, Aly, E, Amarapurkar, Dn, Amougou, N, Amouyel, P, Andersen, Lb, Anderssen, Sa, Anjana, Rm, Ansari-Moghaddam, A, Ansong, D, Aounallah-Skhiri, H, Araujo, J, Ariansen, I, Aris, T, Arku, Re, Arlappa, N, Aryal, Kk, Aspelund, T, Assah, Fk, Assuncao, Mcf, Auvinen, J, Avdicova, M, Azevedo, A, Azimi-Nezhad, M, Azizi, F, Azmin, M, Babu, Bv, Bahijri, S, Balakrishna, N, Bamoshmoosh, M, Banach, M, Banadinovic, M, Bandosz, P, Banegas, Jr, Baran, J, Barbagallo, Cm, Barcelo, A, Barkat, A, Barreto, M, Barros, Ajd, Barros, Mvg, Bartosiewicz, A, Basit, A, Bastos, Jld, Bata, I, Batieha, Am, Batyrbek, A, Baur, La, Beaglehole, R, Belavendra, A, Ben Romdhane, H, Benet, M, Benson, Ls, Berkinbayev, S, Bernabe-Ortiz, A, Bettiol, H, Bezerra, J, Bhagyalaxmi, A, Bhargava, Sk, Bia, D, Biasch, K, Lele, Ecb, Bikbov, Mm, Bista, B, Bjerregaard, P, Bjertness, E, Bjertness, Mb, Bjorkelund, C, Bloch, Kv, Blokstra, A, Bo, S, Bobak, M, Boeing, H, Boggia, Jg, Boissonnet, Cp, Bojesen, Se, Bongard, V, Bonilla-Vargas, A, Bopp, M, Borghs, H, Bovet, P, Boyer, Cb, Braeckman, L, Brajkovich, I, Branca, F, Breckenkamp, J, Brenner, H, Brewster, Lm, Briceno, Y, Brito, M, Bruno, G, Bueno-de-Mesquita, Hb, Bueno, G, Bugge, A, Burns, C, Bursztyn, M, de Leon, Ac, Cacciottolo, J, Cameron, C, Can, G, Candido, Apc, Capanzana, Mv, Capkova, N, Capuano, E, Capuano, V, Cardoso, Vc, Carlsson, Ac, Carvalho, J, Casanueva, Ff, Censi, L, Cervantes-Loaiza, M, Chadjigeorgiou, Ca, Chamukuttan, S, Chan, Aw, Chan, Q, Chaturvedi, Hk, Chaturvedi, N, Chee, Ml, Chen, Cj, Chen, Ff, Chen, Hs, Chen, Sh, Chen, Zm, Cheng, Cy, Cheraghian, B, Dekkaki, Ic, Chetrit, A, Chien, Kl, Chiolero, A, Chiou, St, Chirita-Emandi, A, Chirlaque, Md, Cho, B, Christensen, K, Christofaro, Dg, Chudek, J, Cinteza, E, Claessens, F, Clarke, J, Clays, E, Cohen, E, Concin, H, Cooper, C, Coppinger, Tc, Costanzo, S, Cottel, D, Cowell, C, Craig, Cl, Crampin, Ac, Crujeiras, Ab, Cruz, Jj, Csilla, S, Cui, Lf, Cureau, Fv, Cuschieri, S, D'Arrigo, G, D'Orsi, E, Dallongeville, J, Dankner, R, Dantoft, Tm, Dauchet, L, Davletov, K, De Backer, G, De Bacquer, D, De Curtis, A, de Gaetano, G, De Henauw, S, de Oliveira, Pd, De Ridder, D, De Smedt, D, Deepa, M, Deev, Ad, Degennaro, V, Delisle, H, Demarest, S, Dennison, E, Deschamps, V, Dhimal, M, Di Castelnuovo, Af, Dias-da-Costa, Js, Diaz, A, Dickerson, Tt, Dika, Z, Djalalinia, S, Htp, Do, Dobson, Aj, Donfrancesco, C, Donoso, Sp, Doring, A, Dorobantu, M, Dorr, M, Doua, K, Dragano, N, Drygas, W, Duante, Ca, Duboz, P, Duda, Rb, Dulskiene, V, Dushpanova, A, Dzakula, A, Dzerve, V, Dziankowska-Zaborszczyk, E, Eddie, R, Eftekhar, E, Eggertsen, R, Eghtesad, S, Eiben, G, Ekelund, U, El-Khateeb, M, El Ati, J, Eldemire-Shearer, D, Eliasen, M, Elosua, R, Erasmus, Rt, Erbel, R, Erem, C, Eriksen, L, Eriksson, Jg, Escobedo-de la Pena, J, Eslami, S, Esmaeili, A, Evans, A, Faeh, D, Fakhretdinova, Aa, Fall, Ch, Faramarzi, E, Farjam, M, Fattahi, Mr, Fawwad, A, Felix-Redondo, Fj, Felix, Sb, Ferguson, Ts, Fernandes, Ra, Fernandez-Berges, D, Ferrante, D, Ferrao, T, Ferrari, M, Ferrario, Mm, Ferreccio, C, Ferreira, Hs, Ferrer, E, Ferrieres, J, Figueiro, Th, Fink, G, Fischer, K, Foo, Lh, Forsner, M, Fouad, Hm, Francis, Dk, Grego, Franco, Frikke-Schmidt, R, Frontera, G, Fuchs, Fd, Fuchs, Sc, Fujita, Y, Fumihiko, M, Furdela, V, Furer, A, Furusawa, T, Gaciong, Z, Galbarczyk, A, Galenkamp, H, Galvano, F, Gao, Jl, Gao, P, Garcia-de-la-Hera, M, Garcia, P, Gareta, D, Garnett, Sp, Gaspoz, Jm, Gasull, M, Gazzinelli, A, Gehring, U, Geleijnse, Jm, George, R, Ghanbari, A, Ghasemi, E, Gheorghe-Fronea, Of, Ghimire, A, Gialluisi, A, Giampaoli, S, Gieger, C, Gill, Tk, Giovannelli, J, Gironella, G, Giwercman, A, Gkiouras, K, Goldberg, M, Goldsmith, Ra, Gomez, Lf, Gomula, A, da Silva, Bgc, Goncalves, H, Goncalves, M, Gonzalez-Chica, Da, Gonzalez-Gross, M, Gonzalez-Rivas, Jp, Gonzalez-Villalpando, C, Gonzalez-Villalpando, Me, Gonzalez, Ar, Gorbea, Mb, Gottrand, F, Graff-Iversen, S, Grafnetter, D, Grajda, A, Grammatikopoulou, Mg, Gregor, Rd, Grodzicki, T, Grosso, G, Gruden, G, Df, Gu, Guan, Op, Gudmundsson, Ef, Gudnason, V, Guerrero, R, Guessous, I, Guimaraes, Al, Gulliford, Mc, Gunnlaugsdottir, J, Gunter, Mj, 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Life, APH - Societal Participation & Health, Public and occupational health, APH - Health Behaviors & Chronic Diseases, VU University medical center, APH - Personalized Medicine, Psychiatry, APH - Mental Health, Bin Zhou, Rodrigo M Carrillo-Larco, Goodarz Danaei, Leanne M Riley, Christopher J Paciorek, Gretchen A Stevens, Edward W Gregg, James E Bennett, Bethlehem Solomon, Rosie K Singleton, Marisa K Sophiea, Maria Lc Iurilli, Victor Pf Lhoste, Melanie J Cowan, Stefan Savin, Mark Woodward, Yulia Balanova, Renata Cifkova, Albertino Damasceno, Paul Elliott, Farshad Farzadfar, Jiang He, Nayu Ikeda, Andre P Kengne, Young-Ho Khang, Hyeon Chang Kim, Avula Laxmaiah, Hsien-Ho Lin, Paula Margozzini Maira, J Jaime Miranda, Hannelore Neuhauser, Johan Sundström, Cherian Varghese, Indah S Widyahening, Tomasz Zdrojewski, Leandra Abarca-Gómez, Ziad A Abdeen, Hanan F Abdul Rahim, Niveen M Abu-Rmeileh, Benjamin Acosta-Cazares, Robert J Adams, Wichai Aekplakorn, Kaosar Afsana, Shoaib Afzal, Imelda A 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Huybrechts, Nahla Hwalla, Licia Iacoviello, Anna G Iannone, Mohsen M Ibrahim, Norazizah Ibrahim Wong, M Arfan Ikram, Violeta Iotova, Vilma E Irazola, Takafumi Ishida, Godsent C Isiguzo, Muhammad Islam, Sheikh Mohammed Shariful Islam, Masanori Iwasaki, Rod T Jackson, Jeremy M Jacobs, Hashem Y Jaddou, Tazeen Jafar, Kenneth James, Konrad Jamrozik, Imre Janszky, Edward Janus, Marjo-Riitta Jarvelin, Grazyna Jasienska, Ana Jelaković, Bojan Jelaković, Garry Jennings, Anjani Kumar Jha, Chao Qiang Jiang, Ramon O Jimenez, Karl-Heinz Jöckel, Michel Joffres, Mattias Johansson, Jari J Jokelainen, Jost B Jonas, Torben Jørgensen, Pradeep Joshi, Farahnaz Joukar, Jacek Jóżwiak, Anne Juolevi, Gregor Jurak, Vesna Jureša, Rudolf Kaaks, Anthony Kafatos, Eero O Kajantie, Zhanna Kalmatayeva, Natasa Kalpourtzi, Ofra Kalter-Leibovici, Freja B Kampmann, Srinivasan Kannan, Eva Karaglani, Line L Kårhus, Khem B Karki, Marzieh Katibeh, Joanne Katz, Jussi Kauhanen, Prabhdeep Kaur, Maryam Kavousi, Gyulli M 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William A Neal, Azim Nejatizadeh, Ilona Nenko, Martin Neovius, Chung T Nguyen, Nguyen D Nguyen, Quang V Nguyen, Quang Ngoc Nguyen, Ramfis E Nieto-Martínez, Teemu J Niiranen, Yury P Nikitin, Toshiharu Ninomiya, Sania Nishtar, Marina A Njelekela, Marianna Noale, Oscar A Noboa, Ahmad Ali Noorbala, Teresa Norat, Maria Nordendahl, Børge G Nordestgaard, Noto Davide, Natalia Nowak-Szczepanska, Mohannad Al Nsour, Baltazar Nunes, Terence W O'Neill, Dermot O'Reilly, Caleb Ochimana, Eiji Oda, Augustine N Odili, Kyungwon Oh, Kumiko Ohara, Ryutaro Ohtsuka, Valérie Olié, Maria Teresa A Olinto, Isabel O Oliveira, Mohd Azahadi Omar, Altan Onat, Sok King Ong, Lariane M Ono, Pedro Ordunez, Rui Ornelas, Pedro J Ortiz, Clive Osmond, Sergej M Ostojic, Afshin Ostovar, Johanna A Otero, Kim Overvad, Ellis Owusu-Dabo, Fred Michel Paccaud, Cristina Padez, Elena Pahomova, Karina Mary de Paiva, Andrzej Pająk, Domenico Palli, Luigi Palmieri, Wen-Harn Pan, Songhomitra Panda-Jonas, Francesco Panza, Mariela Paoli, Dimitrios Papandreou, Soon-Woo Park, Suyeon Park, Winsome R Parnell, Mahboubeh Parsaeian, Patrick Pasquet, Nikhil D Patel, Halyna Pavlyshyn, Ivan Pećin, Mangesh S Pednekar, João M Pedro, Nasheeta Peer, Sergio Viana Peixoto, Markku Peltonen, Alexandre C Pereira, Karen Gda Peres, Marco A Peres, Annette Peters, Janina Petkeviciene, Niloofar Peykari, Son Thai Pham, Rafael N Pichardo, Iris Pigeot, Hynek Pikhart, Aida Pilav, Lorenza Pilotto, Freda Pitakaka, Aleksandra Piwonska, Andreia N Pizarro, Pedro Plans-Rubió, Ozren Polašek, Miquel Porta, Anil Poudyal, Farhad Pourfarzi, Akram Pourshams, Hossein Poustchi, Rajendra Pradeepa, Alison J Price, Jacqueline F Price, Rui Providencia, Soile E Puhakka, Maria Puiu, Margus Punab, Radwan F Qasrawi, Mostafa Qorbani, Daniel Queiroz, Tran Quoc Bao, Ivana Radić, Ricardas Radisauskas, Salar Rahimikazerooni, Mahfuzar Rahman, Olli Raitakari, Manu Raj, Ellina M Rakhimova, Sudha Ramachandra Rao, Ambady Ramachandran, Elisabete Ramos, Lekhraj Rampal, Sanjay 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Krishna, Kurjata, Pawel, Kusuma, Yadlapalli S., Kutsenko, Vladimir, Kuulasmaa, Kari, Kyobutungi, Catherine, Laatikainen, Tiina, Lachat, Carl, Laid, Youcef, Lam, Tai Hing, Landrove, Orlando, Lanska, Vera, Lappas, Georg, Larijani, Bagher, Latt, Tint Swe, Le Coroller, Gwenaelle, Khanh Le Nguyen Bao, Le, Tuyen D., Lee, Jeannette, Lee, Jeonghee, Lehmann, Nils, Lehtimaki, Terho, Lemogoum, Daniel, Levitt, Naomi S., Li, Yanping, Lilly, Christa L., Lim, Wei-Yen, Lima-Costa, M. Fernanda, Lin, Xu, Lin, Yi-Ting, Lind, Lars, Lingam, Vijaya, Linneberg, Allan, Lissner, Lauren, Litwin, Mieczyslaw, Lo, Wei-Cheng, Loit, Helle-Mai, Lopez-Garcia, Esther, Lopez, Tania, Lotufo, Paulo A., Lozano, Jose Eugenio, Lovrencic, Iva Lukacevic, Lukrafka, Janice L., Luksiene, Dalia, Lundqvist, Annamari, Lundqvist, Robert, Lunet, Nuno, Lustigova, Michala, Luszczki, Edyta, Ma, Guansheng, Ma, Jun, Machado-Coelho, George L. L., Machado-Rodrigues, Aristides M., Macia, Enguerran, Macieira, Luisa M., Madar, Ahmed A., Maggi, Stefania, Magliano, Dianna J., Magriplis, Emmanuella, Mahasampath, Gowri, Maire, Bernard, Majer, Marjeta, Makdisse, Marcia, Malekzadeh, Fatemeh, Malekzadeh, Reza, Malhotra, Rahul, Mallikharjuna, Kodavanti, Malyutina, Sofia K., Maniego, Lynell V., Manios, Yannis, Mann, Jim I., Mansour-Ghanaei, Fariborz, Manzato, Enzo, Marcil, Anie, Margozzini, Paula, Marild, Staffan B., Glavic, Mihalea Marinovic, Marques-Vidal, Pedro, Marques, Larissa Pruner, Marrugat, Jaume, Martorell, Reynaldo, Mascarenhas, Luis P., Matasin, Marija, Mathiesen, Ellisiv B., Mathur, Prashant, Matijasevich, Alicia, Matlosz, Piotr, Matsha, Tandi E., Mavrogianni, Christina, Mbanya, Jean Claude N., Mc Donald Posso, Anselmo J., McFarlane, Shelly R., McGarvey, Stephen T., McLachlan, Stela, McLean, Rachael M., McLean, Scott B., McNulty, Breige A., Benchekor, Sounnia Mediene, Medzioniene, Jurate, Mehdipour, Parinaz, Mehlig, Kirsten, Mehrparvar, Amir Houshang, Meirhaeghe, Aline, Meisinger, Christa, Mendoza Montano, Carlos, Menezes, Ana Maria B., Menon, Geetha R., Mereke, Alibek, Meshram, Indrapal I., Metspalu, Andres, Meyer, Haakon E., Mi, Jie, Michels, Nathalie, Mikkel, Kairit, Milkowska, Karolina, Miller, Jody C., Minderico, Claudia S., Mini, G. K., Mirjalili, Mohammad Reza, Mirrakhimov, Erkin, Misigoj-Durakovic, Marjeta, Modesti, Pietro A., Moghaddam, Sahar Saeedi, Mohajer, Bahram, Mohamed, Mostafa K., Mohamed, Shukri F., Mohammad, Kazem, Mohammadi, Mohammad Reza, Mohammadi, Zahra, Mohammadifard, Noushin, Mohammadpourhodki, Reza, Mohan, Viswanathan, Mohanna, Salim, Yusoff, Muhammad Fadhli Mohd, Mohebbi, Iraj, Mohebi, Farnam, Moitry, Marie, Mollehave, Line T., Molnar, Denes, Momenan, Amirabbas, Mondo, Charles K., Monterrubio-Flores, Eric, Monyeki, Kotsedi Daniel K., Moon, Jin Soo, Moosazadeh, Mahmood, Moreira, Leila B., Morejon, Alain, Moreno, Luis A., Morgan, Karen, Moschonis, George, Mossakowska, Malgorzata, Mostafa, Aya, Mostafavi, Seyed-Ali, Mota, Jorge, Motlagh, Mohammad Esmaeel, Motta, Jorge, Andre Moura-dos-Santos, Marcos, Mridha, Malay K., Msyamboza, Kelias P., Mu, Thet Thet, Muhihi, Alfa J., Muiesan, Maria L., Muller-Nurasyid, Martina, Murphy, Neil, Mursu, Jaakko, Musa, Kamarul Imran, Milanovic, Sanja Music, Musil, Vera, Mustafa, Norlaila, Nabipour, Iraj, Naderimagham, Shohreh, Nagel, Gabriele, Naidu, Balkish M., Najafi, Farid, Nakamura, Harunobu, Namesna, Jana, Nang, Ei Ei K., Nangia, Vinay B., Narake, Sameer, Ndiaye, Ndeye Coumba, Neal, William A., Nejatizadeh, Azim, Nenko, Ilona, Neovius, Martin, Neuhauser, Hannelore K., Nguyen, Chung T., Nguyen, Nguyen D., Nguyen, Quang V., Quang Ngoc Nguyen, Nieto-Martinez, Ramfis E., Niiranen, Teemu J., Nikitin, Yury P., Ninomiya, Toshiharu, Nishtar, Sania, Njelekela, Marina A., Noale, Marianna, Noboa, Oscar A., Noorbala, Ahmad Ali, Norat, Teresa, Nordendahl, Maria, Nordestgaard, Borge G., Noto, Davide, Nowak-Szczepanska, Natalia, Al Nsour, Mohannad, Nunes, Baltazar, O'Neill, Terence W., O'Reilly, Dermot, Ochimana, Caleb, Oda, Eiji, Odili, Augustine N., Oh, Kyungwon, Ohara, Kumiko, Ohtsuka, Ryutaro, Olie, Valerie, Olinto, Maria Teresa A., Oliveira, Isabel O., Omar, Mohd Azahadi, Onat, Altan, Ong, Sok King, Ono, Lariane M., Ordunez, Pedro, Ornelas, Rui, Ortiz, Pedro J., Osmond, Clive, Ostojic, Sergej M., Ostovar, Afshin, Otero, Johanna A., Overvad, Kim, Owusu-Dabo, Ellis, Paccaud, Fred Michel, Padez, Cristina, Pahomova, Elena, de Paiva, Karina Mary, Pajak, Andrzej, Palli, Domenico, Palmieri, Luigi, Pan, Wen-Harn, Panda-Jonas, Songhomitra, Panza, Francesco, Paoli, Mariela, Papandreou, Dimitrios, Park, Soon-Woo, Park, Suyeon, Parnell, Winsome R., Parsaeian, Mahboubeh, Pasquet, Patrick, Patel, Nikhil D., Pavlyshyn, Halyna, Pecin, Ivan, Pednekar, Mangesh S., Pedro, Joao M., Peer, Nasheeta, Peixoto, Sergio Viana, Peltonen, Markku, Pereira, Alexandre C., Peres, Karen G. D. A., Peres, Marco A., Peters, Annette, Petkeviciene, Janina, Peykari, Niloofar, Son Thai Pham, Pichardo, Rafael N., Pigeot, Iris, Pikhart, Hynek, Pilav, Aida, Pilotto, Lorenza, Pitakaka, Freda, Piwonska, Aleksandra, Pizarro, Andreia N., Plans-Rubio, Pedro, Polasek, Ozren, Porta, Miquel, Poudyal, Anil, Pourfarzi, Farhad, Pourshams, Akram, Poustchi, Hossein, Pradeepa, Rajendra, Price, Alison J., Price, Jacqueline F., Providencia, Rui, Puhakka, Soile E., Puiu, Maria, Punab, Margus, Qasrawi, Radwan F., Qorbani, Mostafa, Queiroz, Daniel, Tran Quoc Bao, Radic, Ivana, Radisauskas, Ricardas, Rahimikazerooni, Salar, Rahman, Mahfuzar, Raitakari, Olli, Raj, Manu, Rakhimova, Ellina M., Rao, Sudha Ramachandra, Ramachandran, Ambady, Ramos, Elisabete, Rampal, Lekhraj, Rampal, Sanjay, Rangel Reina, Daniel A., Rarra, Vayia, Rech, Cassiano Ricardo, Redon, Josep, Reganit, Paul Ferdinand M., Regecova, Valeria, Revilla, Luis, Rezaianzadeh, Abbas, Ribeiro, Robespierre, Riboli, Elio, Richter, Adrian, Rigo, Fernando, de Wit, Tobias F. Rinke, Ritti-Dias, Raphael M., Robitaille, Cynthia, Rodriguez-Artalejo, Fernando, del Cristo Rodriguez-Perez, Maria, Rodriguez-Villamizar, Laura A., Roggenbuck, Ulla, Rojas-Martinez, Rosalba, Romaguera, Dora, Romeo, Elisabetta L., Rosengren, Annika, Roy, Joel G. R., Rubinstein, Adolfo, Ruidavets, Jean-Bernard, Sandra Ruiz-Betancourt, Blanca, Ruiz-Castell, Maria, Rusakova, Iuliia A., Russo, Paola, Rutkowski, Marcin, Sabanayagam, Charumathi, Sabbaghi, Hamideh, Sachdev, Harshpal S., Sadjadi, Alireza, Safarpour, Ali Reza, Safi, Sare, Safiri, Saeid, Saidi, Olfa, Saki, Nader, Salanave, Benoit, Salazar Martinez, Eduardo, Salmeron, Diego, Salomaa, Veikko, Salonen, Jukka T., Salvetti, Massimo, Sanchez-Abanto, Jose, Sans, Susana, Santos, Diana A., Santos, Ina S., Santos, Lelita C., Santos, Maria Paula, Santos, Rute, Saramies, Jouko L., Sardinha, Luis B., Sarganas, Giselle, Sarrafzadegan, Nizal, Sathish, Thirunavukkarasu, Saum, Kai-Uwe, Savva, Savvas, Sawada, Norie, Sbaraini, Mariana, Scazufca, Marcia, Schaan, Beatriz D., Schargrodsky, Herman, Schipf, Sabine, Schmidt, Carsten O., Schnohr, Peter, Schoettker, Ben, Schramm, Sara, Schultsz, Constance, Schutte, Aletta E., Sebert, Sylvain, Sein, Aye Aye, Sen, Abhijit, Senbanjo, Idowu O., Sepanlou, Sadaf G., Servais, Jennifer, Shalnova, Svetlana A., Shamah-Levy, Teresa, Shamshirgaran, Morteza, Shanthirani, Coimbatore Subramaniam, Sharafkhah, Maryam, Sharma, Sanjib K., Shaw, Jonathan E., Shayanrad, Amaneh, Shayesteh, Ali Akbar, Shi, Zumin, Shibuya, Kenji, Shimizu-Furusawa, Hana, Shin, Dong Wook, Shirani, Majid, Shiri, Rahman, Shrestha, Namuna, Si-Ramlee, Khairil, Siani, Alfonso, Siantar, Rosalynn, Sibai, Abla M., de Moura Silva, Caroline Ramos, Santos Silva, Diego Augusto, Simon, Mary, Simons, Judith, Simons, Leon A., Sjostrom, Michael, Slowikowska-Hilczer, Jolanta, Slusarczyk, Przemyslaw, Smeeth, Liam, So, Hung-Kwan, Soares, Fernanda Cunha, Sobngwi, Eugene, Soderberg, Stefan, Soemantri, Agustinus, Sofat, Reecha, Solfrizzi, Vincenzo, Somi, Mohammad Hossein, Sonestedt, Emily, Song, Yi, Sorensen, Thorkild I. A., Sorgjerd, Elin P., Soric, Maroje, Jerome, Charles Sossa, Soumare, Aicha, Sparboe-Nilsen, Bente, Sparrenberger, Karen, Staessen, Jan A., Starc, Gregor, Stavreski, Bill, Steene-Johannessen, Jostein, Stehle, Peter, Stein, Aryeh D., Stergiou, George S., Stessman, Jochanan, Stieber, Jutta, Stoeckl, Doris, Stocks, Tanja, Stokwiszewski, Jakub, Stronks, Karien, Strufaldi, Maria Wany, Suka, Machi, Sun, Chien-An, Sung, Yn-Tz, Suriyawongpaisal, Paibul, Sy, Rody G., Syddall, Holly E., Sylva, Rene Charles, Szklo, Moyses, Tai, E. Shyong, Tammesoo, Mari-Liis, Tamosiunas, Abdonas, Tan, Eng Joo, Tang, Xun, Tanser, Frank, Tao, Yong, Tarawneh, Mohammed Rasoul, Tarqui-Mamani, Carolina B., Taylor, Anne, Taylor, Julie, Tebar, William R., Tell, Grethe S., Tello, Tania, Tham, Yih Chung, Thankappan, K. R., Theobald, Holger, Theodoridis, Xenophon, Thinggaard, Mikael, Thomas, Nihal, Thorand, Barbara, Thuesen, Betina H., Timmermans, Erik J., Tjandrarini, Dwi H., Tjonneland, Anne, Toft, Ulla, Tolonen, Hanna K., Tolstrup, Janne S., Topbas, Murat, Topor-Madry, Roman, Jose Tormo, Maria, Tornaritis, Michael J., Torrent, Maties, Torres-Collado, Laura, Touloumi, Giota, Traissac, Pierre, Triantafyllou, Areti, Trichopoulos, Dimitrios, Trichopoulou, Antonia, Trinh, Oanh T. H., Trivedi, Atul, Tshepo, Lechaba, Tsugane, Shoichiro, Tuliakova, Azaliia M., Tulloch-Reid, Marshall K., Tullu, Fikru, Tuomainen, Tomi-Pekka, Tuomilehto, Jaakko, Turley, Maria L., Twig, Gilad, Tynelius, Per, Tzourio, Christophe, Ueda, Peter, Ugel, Eunice, Ulmer, Hanno, Uusitalo, Hannu M. T., Valdivia, Gonzalo, Valvi, Damaskini, van Dam, Rob M., van den Born, Bert-Jan, Van der Heyden, Johan, van der Schouw, Yvonne T., Van Herck, Koen, Hoang Van Minh, Van Schoor, Natasja M., van Valkengoed, Irene G. M., van Zutphen, Elisabeth M., Vanuzzo, Diego, Varbo, Anette, Vasan, Senthil K., Vega, Tomas, Veidebaum, Toomas, Velasquez-Melendez, Gustavo, Veronesi, Giovanni, Verschuren, W. M. Monique, Verstraeten, Roosmarijn, Victora, Cesar G., Viet, Lucie, Villalpando, Salvador, Vineis, Paolo, Vioque, Jesus, Virtanen, Jyrki K., Visvikis-Siest, Sophie, Viswanathan, Bharathi, Vlasoff, Tiina, Vollenweider, Peter, Voutilainen, Ari, Wade, Alisha N., Walton, Janette, Wambiya, Elvis O. A., Bebakar, Wan Mohamad Wan, Mohamud, Wan Nazaimoon Wan, Wanderley Junior, Rildo de Souza, Wang, Ming-Dong, Wang, Ningli, Wang, Qian, Wang, Xiangjun, Wang, Ya Xing, Wang, Ying-Wei, Wannamethee, S. Goya, Wareham, Nicholas, Wei, Wenbin, Weres, Aneta, Werner, Bo, Whincup, Peter H., Widhalm, Kurt, Wiecek, Andrzej, Wilks, Rainford J., Willeit, Johann, Willeit, Peter, Williams, Emmanuel A., Wilsgaard, Tom, Wojtyniak, Bogdan, Wong-McClure, Roy A., Wong, Andrew, Wong, Tien Yin, Woo, Jean, Wu, Frederick C., Wu, Shouling, Wyszynska, Justyna, Xu, Haiquan, Xu, Liang, Yaacob, Nor Azwany, Yan, Weili, Yang, Ling, Yang, Xiaoguang, Yang, Yang, Yasuharu, Tabara, Ye, Xingwang, Yiallouros, Panayiotis K., Yoosefi, Moein, Yoshihara, Akihiro, You, San-Lin, Younger-Coleman, Novie O., Yusoff, Ahmad Faudzi, Zainuddin, Ahmad A., Zakavi, Seyed Rasoul, Zamani, Farhad, Zambon, Sabina, Zampelas, Antonis, Elisa Zapata, Maria, Zaw, Ko Ko, Zejglicova, Kristyna, Vrkic, Tajana Zeljkovic, Zeng, Yi, Zhang, Luxia, Zhao, Dong, Zhao, Ming-Hui, Zhen, Shiqi, Zheng, Yingfeng, Zholdin, Bekbolat, Zhu, Dan, Zins, Marie, Zitt, Emanuel, Zocalo, Yanina, Zoghlami, Nada, Zuniga Cisneros, Julio., School of Medicine, ACS - Diabetes & metabolism, APH - Global Health, Pulmonology, Medical Informatics, Adult Psychiatry, Global Health, APH - Quality of Care, APH - Methodology, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, Anesthesiology, Graduate School, and ACS - Heart failure & arrhythmias

Subjects
Male, Latin Americans, Nutrition and Disease, Epidemiology, [SDV]Life Sciences [q-bio], Medizin, BLOOD-PRESSURE, 030204 cardiovascular system & hematology, Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants, Hypertension, Prevalence, Control, Tretament, GUIDELINES, Global Health, Worldwide trends, 0302 clinical medicine, Hypertension prevalence, Voeding en Ziekte, Medicine and Health Sciences, kohonnut verenpaine, Medicine, 030212 general & internal medicine, Prevention and Control, 11 Medical and Health Sciences, ComputingMilieux_MISCELLANEOUS, education.field_of_study, food and beverages, Public Health, Global Health, Social Medicine and Epidemiology, General Medicine, Noncommunicable diseases, Period prevalence, Middle Aged, kansainvälinen vertailu, 3142 Public health care science, environmental and occupational health, 3. Good health, MIDDLE-INCOME, Pooled analysis, SYSTEMATIC ANALYSIS, INCOME COUNTRIES, ADULTS, PREVENTION, MANAGEMENT, ADHERENCE, DIAGNOSIS, Western europe, [SDE]Environmental Sciences, Hypertension/diagnosis, NCD Risk Factor Collaboration (NCD-RisC), Female, B990 Subjects Allied to Medicine not elsewhere classified, Life Sciences & Biomedicine, Adult, health-care, esiintyvyys, Central asia, Population, Nursing, 3121 Internal medicine, 03 medical and health sciences, Medicine, General & Internal, Drug Therapy, General & Internal Medicine, Life Science, Humans, ddc:610, education, Antihypertensive Agents, VLAG, Aged, Science & Technology, Antihypertensive Agents/therapeutic use, business.industry, Omvårdnad, fungi, General and internal medicine, Estados de Saúde e de Doença, Taking medication, Treatment, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Blood pressure, Faculdade de Ciências Sociais, 3121 General medicine, internal medicine and other clinical medicine, lääkehoito, 1182 Biochemistry, cell and molecular biology, business, Demography
Abstract

Background: hypertension can be detected at the primary health-care level and low-cost treatments can effectively control hypertension. We aimed to measure the prevalence of hypertension and progress in its detection, treatment, and control from 1990 to 2019 for 200 countries and territories. Methods: we used data from 1990 to 2019 on people aged 30-79 years from population-representative studies with measurement of blood pressure and data on blood pressure treatment. We defined hypertension as having systolic blood pressure 140 mm Hg or greater, diastolic blood pressure 90 mm Hg or greater, or taking medication for hypertension. We applied a Bayesian hierarchical model to estimate the prevalence of hypertension and the proportion of people with hypertension who had a previous diagnosis (detection), who were taking medication for hypertension (treatment), and whose hypertension was controlled to below 140/90 mm Hg (control). The model allowed for trends over time to be non-linear and to vary by age. Findings: the number of people aged 30-79 years with hypertension doubled from 1990 to 2019, from 331 (95% credible interval 306-359) million women and 317 (292-344) million men in 1990 to 626 (584-668) million women and 652 (604-698) million men in 2019, despite stable global age-standardised prevalence. In 2019, age-standardised hypertension prevalence was lowest in Canada and Peru for both men and women; in Taiwan, South Korea, Japan, and some countries in western Europe including Switzerland, Spain, and the UK for women; and in several low-income and middle-income countries such as Eritrea, Bangladesh, Ethiopia, and Solomon Islands for men. Hypertension prevalence surpassed 50% for women in two countries and men in nine countries, in central and eastern Europe, central Asia, Oceania, and Latin America. Globally, 59% (55-62) of women and 49% (46-52) of men with hypertension reported a previous diagnosis of hypertension in 2019, and 47% (43-51) of women and 38% (35-41) of men were treated. Control rates among people with hypertension in 2019 were 23% (20-27) for women and 18% (16-21) for men. In 2019, treatment and control rates were highest in South Korea, Canada, and Iceland (treatment >70%; control >50%), followed by the USA, Costa Rica, Germany, Portugal, and Taiwan. Treatment rates were less than 25% for women and less than 20% for men in Nepal, Indonesia, and some countries in sub-Saharan Africa and Oceania. Control rates were below 10% for women and men in these countries and for men in some countries in north Africa, central and south Asia, and eastern Europe. Treatment and control rates have improved in most countries since 1990, but we found little change in most countries in sub-Saharan Africa and Oceania. Improvements were largest in high-income countries, central Europe, and some upper-middle-income and recently high-income countries including Costa Rica, Taiwan, Kazakhstan, South Africa, Brazil, Chile, Turkey, and Iran. Interpretation Improvements in the detection, treatment, and control of hypertension have varied substantially across countries, with some middle-income countries now outperforming most high-income nations. The dual approach of reducing hypertension prevalence through primary prevention and enhancing its treatment and control is achievable not only in high-income countries but also in low-income and middle-income settings., British Heart Foundation Centre of Research Excellence Grant; World Health Organization (WHO); Abdul Latif Jameel Institute for Disease and Emergency Analytics Fellowship

Published
2021
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18. Putative adverse outcome pathways for female reproductive disorders to improve testing and regulation of chemicals

Author

Andres Salumets, Agne Velthut-Meikas, Pauline Lelandais, Séverine Mazaud-Guittot, Marijke de Cock, Panagiotis Filis, Lisa Connolly, Pauliina Damdimopoulou, Julie Boberg, Sofie Christiansen, Majorie B.M. van Duursen, Paul Fowler, Magdalena Wagner, Anne-Simone Parent, Delphine Franssen, Terje Svingen, Hanna Katarina Lilith Johansson, Monica Kam Draskau, Yuling Xie, Kersti Jääger, Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Karolinska Inst, Dept Clinique Sci Intervent and Technology, Div Obstet and Gynecol, Sweden, Karolinska Institutet [Stockholm], Vrije Universiteit Amsterdam [Amsterdam] (VU), GIGA [Université Liège], Université de Liège, Tallinn University of Technology (TTÜ), Queens University Belfast, Sch Biol Sci, Inst Global Food Secur, Belfast BT9 5DL, North Ireland, Queen's University [Belfast] (QUB), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), University of Tartu, University of Aberdeen, Centre Hospitalier Universitaire de Liège (CHU-Liège), EU Horizon 2020 project FREIA [825100], HUS Gynecology and Obstetrics, Clinicum, Department of Obstetrics and Gynecology, University of Helsinki, Helsinki University Hospital Area, Technical University of Denmark [Lyngby] (DTU), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Jonchère, Laurent

Subjects
0301 basic medicine, Health, Toxicology and Mutagenesis, [SDV]Life Sciences [q-bio], ENDOCRINE DISRUPTING CHEMICALS, LESS CONFUSING TERMINOLOGY, Review Article, Safeguarding, Toxicology, Mice, ODS, 0302 clinical medicine, 3123 Gynaecology and paediatrics, Pregnancy, Regulation of chemicals, Adverse Outcome Pathway, Medicine, Ovarian Diseases, Continuous exposure, GENE-EXPRESSION, Reproductive health, Ovarian dysgenesis syndrome, 030219 obstetrics & reproductive medicine, SDG 5 - Gender Equality, BISPHENOL-A EXPOSURE, Reproduction, General Medicine, Chemical Safety, POLYCYSTIC-OVARY-SYNDROME, 3. Good health, [SDV] Life Sciences [q-bio], Reproductive Health, Maternal Exposure, Female, ANTI-MULLERIAN HORMONE, Endocrine System Diseases, Female reproductive disorders, Risk Assessment, Letter to the Editor, News and Views, Birth rate, 03 medical and health sciences, Adverse outcome pathway, SDG 3 - Good Health and Well-being, Environmental health, PRIMORDIAL FOLLICLE, Toxicity Tests, Animals, Humans, AOP, ORGANOCHLORINE PESTICIDES, Endocrine-disrupting chemicals, Adverse Outcome Pathways, business.industry, Ovary, Review article, GERM-CELL, 030104 developmental biology, IN-UTERO EXPOSURE, 3111 Biomedicine, business, EDC
Abstract

Modern living challenges female reproductive health. We are witnessing a rise in reproductive disorders and drop in birth rates across the world. The reasons for these manifestations are multifaceted and most likely include continuous exposure to an ever-increasing number of chemicals. The cause–effect relationships between chemical exposure and female reproductive disorders, however, have proven problematic to determine. This has made it difficult to assess the risks chemical exposures pose to a woman’s reproductive development and function. To address this challenge, this review uses the adverse outcome pathway (AOP) concept to summarize current knowledge about how chemical exposure can affect female reproductive health. We have a special focus on effects on the ovaries, since they are essential for lifelong reproductive health in women, being the source of both oocytes and several reproductive hormones, including sex steroids. The AOP framework is widely accepted as a new tool for toxicological safety assessment that enables better use of mechanistic knowledge for regulatory purposes. AOPs equip assessors and regulators with a pragmatic network of linear cause–effect relationships, enabling the use of a wider range of test method data in chemical risk assessment and regulation. Based on current knowledge, we propose ten putative AOPs relevant for female reproductive disorders that can be further elaborated and potentially be included in the AOPwiki. This effort is an important step towards better safeguarding the reproductive health of all girls and women.

Published
2020
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19. Safeguarding female reproductive health against endocrine disrupting chemicals—The FREIA project

Author

van Duursen, Majorie B.M., Boberg, Julie, Christiansen, Sofie, Connolly, Lisa, Damdimopoulou, Pauliina, Filis, Panagiotis, Fowler, Paul A., Gadella, Bart M., Holte, Jan, Jääger, Kersti, Johansson, Hanna K.L., Li, Tianyi, Mazaud-Guittot, Séverine, Parent, Anne Simone, Salumets, Andres, Soto, Ana M., Svingen, Terje, Velthut-Meikas, Agne, Wedebye, Eva Bay, Xie, Yuling, van den Berg, Martin, One Health Toxicologie, FAH klinische reproductie, Veterinaire biochemie, dB&C FR-RMSC FR, dES/dFAH FR, IRAS OH Toxicology, dIRAS RA-1, One Health Toxicologie, FAH klinische reproductie, Veterinaire biochemie, dB&C FR-RMSC FR, dES/dFAH FR, IRAS OH Toxicology, dIRAS RA-1, E&H: Environmental Health and Toxicology, AIMMS, Vrije Universiteit Amsterdam [Amsterdam] (VU), Tech University Denmark, National Food Inst, Denmark, Technical University of Denmark [Lyngby] (DTU), Queens University Belfast, Sch Biol Sci, Inst Global Food Secur, Belfast BT9 5DL, North Ireland, Queen's University [Belfast] (QUB), Karolinska Inst, Dept Clinique Sci Intervent and Technology, Div Obstet and Gynecol, Sweden, CHU Stockholm, Karolinska Institutet [Stockholm], Inst Med Sci, Sch Med Med Sci and Nutr, Foresterhill, Scotland, University of Aberdeen, UniversiteitUtrecht, Fac Vet Med, Dept Populat Hlth Sci, Yalelaan 2, Netherlands, Utrecht University [Utrecht], Carl von Linne Clinique, Uppsala Sci Pk, Sweden, Competence Centre Hlth Technology, Teaduspargi 13, Estonia, University of Tartu, Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), University Liege, [GIGA] Inst, Neuroendocrinol Unit, Ave Hôpital, Belgium, GIGA [Université Liège], Université de Liège, Tufts University [Medford], Tallinn University of Technology (TTÜ), European UnionEuropean Union (EU) [825100], Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Jonchère, Laurent

Subjects
0301 basic medicine, Oocyte, [SDV]Life Sciences [q-bio], Endocrine Disruptors, Female reproductive system, Safeguarding, Female reproductive health, lcsh:Chemistry, 0302 clinical medicine, Risk Factors, Adrenal, Endocrine disrupting chemicals, lcsh:QH301-705.5, Spectroscopy, media_common, Reproductive health, Risk assessment, fertility, 030219 obstetrics & reproductive medicine, SDG 5 - Gender Equality, Reproduction, risk assessment, General Medicine, 3. Good health, Computer Science Applications, [SDV] Life Sciences [q-bio], Reproductive Health, medicine.anatomical_structure, Environmental Pollutants, Female, Bioassay, Test methods, Project Report, media_common.quotation_subject, Mammary gland, Endocrine System, Fertility, Ovary, test methods, Catalysis, Inorganic Chemistry, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Environmental health, medicine, Animals, Humans, Endocrine system, Physical and Theoretical Chemistry, Molecular Biology, business.industry, Puberty, Organic Chemistry, Environmental Exposure, endocrine disrupting chemicals, 030104 developmental biology, lcsh:Biology (General), lcsh:QD1-999, Steroidogenesis, Chemical regulation, ovary, business, female reproductive health
Abstract

International audience; Currently available test methods are not well-suited for the identification of chemicals that disturb hormonal processes involved in female reproductive development and function. This renders women's reproductive health at increasing risk globally, which, coupled with increasing incidence rates of reproductive disorders, is of great concern. A woman's reproductive health is largely established during embryonic and fetal development and subsequently matures during puberty. The endocrine system influences development, maturation, and function of the female reproductive system, thereby making appropriate hormone levels imperative for correct functioning of reproductive processes. It is concerning that the effects of human-made chemicals on the endocrine system and female reproductive health are poorly addressed in regulatory chemical safety assessment, partly because adequate test methods are lacking. Our EU-funded project FREIA aims to address this need by increasing understanding of how endocrine disrupting chemicals (EDCs) can impact female reproductive health. We will use this information to provide better test methods that enable fit-for-purpose chemical regulation and then share our knowledge, promote a sustainable society, and improve the reproductive health of women globally.

Published
2020
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20. Baseline Characteristics of Patients With Heart Failure and Preserved Ejection Fraction in the PARAGON-HF Trial

Author

Faiez Zannad, Andreas J. Flammer, Lars Køber, Yoshihiko Saito, Inder S. Anand, Turia Ben-Gal, Adel R. Rizkala, Davor Miličić, Hans Dirk Duengen, Nancy K. Sweitzer, Junbo Ge, Jiří Widimský, Tzvetana Katova, Robert Zweiker, Chen Huan Chen, Sergio V. Perrone, Margaret M. Redfield, Sanjiv J. Shah, Michael R. Zile, Milton Packer, Jean L. Rouleau, Felipe Martinez, Michele Senni, Juan Luis Arango, Gerard Linssen, Eileen O'Meara, Vijay K. Chopra, Aldo P. Maggioni, Josep Comín-Colet, Bojan Vrtovec, Stefan D. Anker, Jyrki Taurio, Armando Godoy, Scott D. Solomon, Jingmin Zhou, David Sim, Małgorzata Lelonek, Dragos Vinereanu, Michel Galinier, John J.V. McMurray, Carolyn S.P. Lam, Naresh Ranjith, Burkert Pieske, Nagesh S. Anavekar, Béla Merkely, Jose L. Arenas, Sergey Boytsov, John G.F. Cleland, José Francisco Kerr Saraiva, Stefan Janssens, Jianjian Gong, Victor Shi, Dirk J. van Veldhuisen, Eva Goncalvesova, Antonio S. Sibulo, Petar M. Seferovic, Martin Lefkowitz, Byung Hee Oh, Mehmet Yilmaz, Luis E. Echeverría Correa, Marc A. Pfeffer, Lars Lund, Dan Atar, Gerasimos Filippatos, Cardiovascular Centre (CVC), Solomon, S, Rizkala, A, Lefkowitz, M, Shi, V, Gong, J, Anavekar, N, Anker, S, Arango, J, Arenas, J, Atar, D, Ben-Gal, T, Boytsov, S, Chen, C, Chopra, V, Cleland, J, Comin-Colet, J, Duengen, H, Echeverria Correa, L, Filippatos, G, Flammer, A, Galinier, M, Godoy, A, Goncalvesova, E, Janssens, S, Katova, T, Kober, L, Lelonek, M, Linssen, G, Lund, L, O'Meara, E, Merkely, B, Milicic, D, Oh, B, Perrone, S, Ranjith, N, Saito, Y, Saraiva, J, Shah, S, Seferovic, P, Senni, M, Sibulo, A, Sim, D, Sweitzer, N, Taurio, J, Vinereanu, D, Vrtovec, B, Widimsky, J, Yilmaz, M, Zhou, J, Zweiker, R, Anand, I, Ge, J, Lam, C, Maggioni, A, Martinez, F, Packer, M, Pfeffer, M, Pieske, B, Redfield, M, Rouleau, J, Van Veldhuisen, D, Zannad, F, Zile, M, Mcmurray, J, [Solomon, Scott D. -- Pfeffer, Marc A.] Harvard Med Sch, Brigham & Womens Hosp, Cardiovasc Div, Boston, MA 02115 USA -- [Rizkala, Adel R. -- Lefkowitz, Martin P. -- Shi, Victor C. -- Gong, JianJian] Novartis Pharmaceut, E Hanover, NJ USA -- [Anavekar, Nagesh] Univ Melbourne, Fac Med Dent & Hlth Sci, Melbourne, Vic, Australia -- [Anker, Stefan D.] Charite Univ Med Berlin, Deutsch Zentrum Herz Kreislauf Forsch DZHK Berlin, Div Cardiol & Metab, Dept Cardiol CVK, Berlin, Germany -- [Anker, Stefan D.] Charite Univ Med Berlin, Deutsch Zentrum Herz Kreislauf Forsch DZHK Berlin, Berlin Brandenburg Ctr Regenerat Therapies BCRT, Berlin, Germany -- [Anker, Stefan D.] Univ Gottingen, Med Ctr, Dept Cardiol & Pneumol, Gottingen, Germany -- [Arango, Juan L.] Guatemalan Heart Inst, San Luis Potosi, Mexico -- [Arango, Juan L.] Ctr Atenc & Invest Cardiovasc Potosi SC, San Luis Potosi, Mexico -- [Arango, Juan L.] Hosp Angeles San Luis, San Luis Potosi, Mexico -- [Atar, Dan] Univ Oslo, Dept Cardiol B, Oslo, Norway -- [Ben-Gal, Turia] Rabin Med Ctr, Cardiol Dept, Heart Failure Unit, Petah Tiqwa, Israel -- [Boytsov, Sergey A.] Minist Hlth Russian Federat, Natl Res Ctr Cardiol, Moscow, Russia -- [Chen, Chen-Huan] Natl Yang Ming Univ, Dept Med, Taipei, Taiwan -- [Chopra, Vijay K.] Medanta Med, Heart Failure Unit, Gurugram, Haryana, India -- [Cleland, John] Univ Glasgow, Inst Hlth & Wellbeing, Robertson Ctr Biostat & Clin Trials, Glasgow, Lanark, Scotland -- [McMurray, John J. V.] Univ Glasgow, British Heart Fdn, Cardiovasc Res Ctr, Glasgow, Lanark, Scotland -- [Cleland, John] Imperial Coll, Royal Brompton & Harefield Hosp, Natl Heart & Lung Inst, London, England -- [Comin-Colet, Josep] Univ Barcelona, Bellvitge Univ Hosp, Dept Cardiol, Community Heart Failure Program, Barcelona, Spain -- [Comin-Colet, Josep] Univ Barcelona, Inst Invest Biomed Bellvitge, Barcelona, Spain -- [Duengen, Hans-Dirk -- Pieske, Burkert] Univ Med Berlin, Cardiol Charite, Dept Internal Med, Campus Virchow Klinikum Berlin, Berlin, Germany -- [Echeverria Correa, Luis E.] Fdn Cardiovasc Colombia, Heart Failure Unit, Santander, Spain -- [Echeverria Correa, Luis E.] Fdn Cardiovasc Colombia, Cardiac Transplant Program, Santander, Spain -- [Filippatos, Gerasimos] Univ Athens, Attikon Univ Hosp, Athens, Greece -- [Filippatos, Gerasimos] Univ Cyprus, Sch Med, Athens, Greece -- [Flammer, Andreas J.] Univ Hosp Zurich, Univ Heart Ctr Zurich, Dept Cardiol, Zurich, Switzerland -- [Galinier, Michel] Rangueil Univ Hosp, Dept Cardiol, Toulouse, France -- [Godoy, Armando] Univ Nacl Mayor San Marcos, Lima, Peru -- [Godoy, Armando] Inst Nacl Cardiovasc INCOR, Lima, Peru -- [Godoy, Armando] Scientia Clin & Epidemiol Res Inst, Trujillo, Peru -- [Goncalvesova, Eva] Natl Cardiovasc Inst, Dept Heart Failure Transplantat, Bratislava, Slovakia -- [Janssens, Stefan] Univ Hosp Leuven, Dept Cardiol, Leuven, Belgium -- [Katova, Tzvetana] Natl Cardiol Hosp, Clin Cardiol, Sofia, Bulgaria -- [Saraiva, Jose F.] Pontificia Univ Catolica Campinas, Fac Med, Disciplina Cardiol, Sao Paulo, Brazil -- [Kober, Lars] Copenhagen Univ Hosp, Rigshosp, Heart Ctr, Dept Cardiol, Copenhagen, Denmark -- [Lelonek, Malgorzata] Med Univ Lodz, Dept Noninvas Cardiol, Lodz, Poland -- [Linssen, Gerard] Hosp Grp Twente, Dept Cardiol, Almelo, Netherlands -- [Linssen, Gerard] Hosp Grp Twente, Dept Cardiol, Hengelo, Netherlands -- [Lund, Lars H.] Karolinska Univ Hosp, Karolinska Inst & Heart & Vasc Theme, Dept Med, Stockholm, Sweden -- [O'Meara, Eileen -- Rouleau, Jean L.] Univ Montreal, Inst Cardiol Montreal, Montreal, PQ, Canada -- [Merkely, Bela] Semmelweis Univ, Heart & Vasc Ctr, Budapest, Hungary -- [Milicic, Davor] Univ Hosp Ctr Zagreb, Dept Cardiovasc Dis, Zagreb, Croatia -- [Oh, Byung-Hee] Seoul Natl Univ, Seoul Natl Univ Hosp, Coll Med, Seoul, South Korea -- [Perrone, Sergio V.] Inst FLENI, Buenos Aires, DF, Argentina -- [Ranjith, Naresh] City Hosp, Dept Cardiol, Durban, South Africa -- [Saito, Yoshihiko] Nara Med Univ, Dept Internal Med 1, Kashihara, Nara, Japan -- [Shah, Sanjiv] Northwestern Univ, Feinberg Sch Med, Dept Med, Div Cardiol, Chicago, IL 60611 USA -- [Seferovic, Petar M.] Univ Belgrade, Med Ctr, Univ Belgrade, Dept Cardiol,Sch Med, Belgrade, Serbia -- [Senni, Michele] Hosp Papa Giovanni XXIII, Cardiovasc Dept, Cardiol Div, Bergamo, Italy -- [Sibulo, Antonio S., Jr.] St Lukes Med Ctr, St Lukes Heart Inst, Taguig, Philippines -- [Sim, David] Natl Heart Ctr Singapore, Dept Cardiol, Singapore, Singapore -- [Sweitzer, Nancy K.] Univ Arizona, Coll Med, Sarver Heart Ctr, Tucson, AZ USA -- [Taurio, Jyrki] Tampere Univ Hosp, Dept Cardiol, Tampere, Finland -- [Vinereanu, Dragos] Univ Med & Pharm Carol Davila, Univ & Emergency Hosp Bucharest, Bucharest, Romania -- [Vrtovec, Bojan] Univ Med Ctr, Ljubljana, Slovenia -- [Widimsky, Jiri] Charles Univ Prague, Fac Med 1, Prague, Czech Republic -- [Yilmaz, Mehmet B.] Cumhuriyet Univ, Fac Med, Dept Cardiol, Sivas, Turkey -- [Zhou, Jingmin] Tongji Univ, Sch Med, Tongji Hosp, Dept Cardiol, Shanghai, Peoples R China -- [Zweiker, Robert] Med Univ Graz, Dept Cardiol, Graz, Austria -- [Anand, Inder S.] VA Med Ctr, Dept Med, Minneapolis, MN USA -- [Anand, Inder S.] Univ Minnesota, Minneapolis, MN USA -- [Ge, Junbo] Fudan Univ, Zhongshan Hosp, Shanghai Inst Cardiovasc Dis, Shanghai, Peoples R China -- [Lam, Carolyn S. P.] Natl Heart Ctr Singapore, Singapore, Singapore -- [Lam, Carolyn S. P.] Duke Natl Univ Singapore, Singapore, Singapore -- [Maggioni, Aldo P.] Associaz Nazl Med Cardiol Osped, Florence, Italy -- [Martinez, Felipe] Univ Nacl Cordoba, Cordoba, Argentina -- [Packer, Milton] Baylor Univ, Med Ctr, Baylor Heart & Vasc Inst, Dallas, TX USA -- [Redfield, Margaret M.] Mayo Clin, Dept Cardiovasc Med, Rochester, MN USA -- [Van Veldhuisen, Dirk J.] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands -- [Zannad, Faiez] INSERM, CIC 1433, Nancy, France -- [Zannad, Faiez] Univ Lorraine, CHR Univ, Nancy, France -- [Zile, Michael R.] Med Univ South Carolina, Charleston, SC 29425 USA -- [Zile, Michael R.] Ralph H Johnson Vet Adm, Med Ctr, Charleston, SC USA, Boytsov, Sergey -- 0000-0001-6998-8406, Maggioni, Aldo Pietro -- 0000-0003-2764-6779, and Anand, Inder -- 0000-0003-1308-4963

Subjects
Male, medicine.medical_specialty, Angiotensin receptor, Adrenergic beta-Antagonists, Diastole, heart failure, Angiotensin-Converting Enzyme Inhibitors, 030204 cardiovascular system & hematology, heart failure, diastolic, Ventricular Function, Left, 03 medical and health sciences, NEPRILYSIN INHIBITION, 0302 clinical medicine, Internal medicine, angiotensin receptor antagonists, Medicine, Humans, 030212 general & internal medicine, 10. No inequality, endopeptidase, Aged, Mineralocorticoid Receptor Antagonists, Aged, 80 and over, antagonists, Clinical Trials as Topic, OUTCOMES, Ejection fraction, Angiotensin Receptor Antagonists, business.industry, Stroke Volume, clinical trial, Middle Aged, angiotensin receptor, medicine.disease, 3. Good health, Clinical trial, endopeptidases, angiotensin receptor antagonist, diastolic, Baseline characteristics, Heart failure, Cardiology, Valsartan, Female, Cardiology and Cardiovascular Medicine, business, Angiotensin II Type 1 Receptor Blockers
Abstract

WOS: 000438926500008, PubMed ID: 29980595, BACKGROUND: To describe the baseline characteristics of patients with heart failure and preserved left ventricular ejection fraction enrolled in the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF) comparing sacubitril/valsartan to valsartan in reducing morbidity and mortality. METHODS AND RESULTS: We report key demographic, clinical, and laboratory findings, and baseline therapies, of 4822 patients randomized in PARAGON-HF, grouped by factors that influence criteria for study inclusion. We further compared baseline characteristics of patients enrolled in PARAGON-HF with those patients enrolled in other recent trials of heart failure with preserved ejection fraction (HFpEF). Among patients enrolled from various regions (16% Asia-Pacific, 37% Central Europe, 7% Latin America, 12% North America, 28% Western Europe), the mean age of patients enrolled in PARAGON-HF was 72.7 +/- 8.4 years, 52% of patients were female, and mean left ventricular ejection fraction was 57.5%, similar to other trials of HFpEF. Most patients were in New York Heart Association class II, and 38% had >= 1 hospitalizations for heart failure within the previous 9 months. Diabetes mellitus (43%) and chronic kidney disease (47%) were more prevalent than in previous trials of HFpEF. Many patients were prescribed angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (85%), beta-blockers (80%), calcium channel blockers (36%), and mineralocorticoid receptor antagonists (24%). As specified in the protocol, virtually all patients were on diuretics, had elevated plasma concentrations of N-terminal pro-B-type natriuretic peptide (median, 911 pg/mL; interquartile range, 464-1610), and structural heart disease. CONCLUSIONS: PARAGON-HF represents a contemporary group of patients with HFpEF with similar age and sex distribution compared with prior HFpEF trials but higher prevalence of comorbidities. These findings provide insights into the impact of inclusion criteria on, and regional variation in, HFpEF patient characteristics., Novartis, The PARAGON-HF trial is funded by Novartis.

Published
2018

21. More than 5000 patients with metastatic melanoma in Europe per year do not have access to recommended first-line innovative treatments

Author

Ketty Peris, Lev V. Demidov, Lars Bastholt, J.-J. Grob, Paul Nathan, M. Banjin, M. Kukushkina, Alexandros Stratigos, A.M. Forsea, A. Ymeri, Matilda Bylaite-Bucinskiene, Christoph Hoeller, A. Zhukavets, V. Todorovic, G. Weinlich, Claus Garbe, K. Putnik, L. Kandolf Sekulovic, Piotr Rutkowski, M. Risteski, K. Kirov, Iris Zalaudek, J. Ocvirk, Reinhard Dummer, D. Herceg, J. Maric-Brozic, Helen Gogas, Ricardo Vieira, Judit Oláh, Ivana Krajsová, N. Babovic, L. De La Cruz Merino, C. Blank, Johan Hansson, Bart Neyns, Axel Hauschild, C. Lebbé, Laboratory of Molecullar and Cellular Therapy, Laboratory for Medical and Molecular Oncology, Clinical sciences, [Sekulovic, L. Kandolf] Mil Med Acad, Fac Med, Dept Dermatol, Belgrade, Serbia, [Peris, K.] Univ Cattolica Sacro Cuore, Inst Dermatol, Rome, Italy, [Hauschild, A.] Univ Hosp Schleswig Holstein UKSH, Dept Dermatol, Campus Kiel, Kiel, Germany, [Stratigos, A.] Univ Athens, Athens, Greece, [Gogas, H.] Univ Athens, Athens, Greece, [Grob, J. -J.] Hop la Timone, Serv Dermatol & Cancerol Cutanee, Marseille, France, [Nathan, P.] Mt Vernon Canc Ctr, Northwood, Middx, England, [Dummer, R.] Univ Hosp, Univ Spital Zurich, Skin Canc Ctr, Zurich, Switzerland, [Forsea, A. -M.] Carol Davila Univ Med & Pharm, Elias Univ Hosp Bucharest, Bucharest, Romania, [Hoeller, C.] Med Univ Vienna, Dept Dermatol, Vienna, Austria, [Demidov, L.] NN Blokhin Russian Canc Res Ctr, Moscow, Russia, [Lebbe, C.] Hosp St Louis, APHP, Paris, France, [Blank, C.] Netherland Canc Inst, Amsterdam, Netherlands, [Olah, J.] Univ Szeged, Dept Dermatol & Allergol, Szeged, Hungary, [Bastholt, L.] Odense Univ Hosp, Dept Oncol, Odense, Denmark, [Herceg, D.] Univ Hosp Zagreb, Dept Oncol, Zagreb, Croatia, [Neyns, B.] VUB, Univ Ziekenhuis Brussel, Dept Med Oncol, Brussels, Belgium, [Vieira, R.] Univ Coimbra, Fac Med, Dept Dermatol, Coimbra, Portugal, [Hansson, J.] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden, [Hansson, J.] Karolinska Univ Hosp Solna, Stockholm, Sweden, [Rutkowski, P.] Maria Sklodowska Curie Mem Canc Ctr, Warsaw, Poland, [Rutkowski, P.] Inst Oncol, Warsaw, Poland, [Krajsova, I.] Gen Teaching Hosp, Prague, Czech Republic, [Bylaite-Bucinskiene, M.] Vilnius Univ, Dept Dermatol, Vilnius, Lithuania, [Zalaudek, I.] Med Univ Graz, Div Dermatol & Venerol, Graz, Austria, [Maric-Brozic, J.] Univ Hosp Ctr Sestre Milosrdnice, Zagreb, Croatia, [Babovic, N.] Inst Oncol & Radiol Serbia, Belgrade, Serbia, [Banjin, M.] Univ Hosp Sarajevo, Dept Oncol, Sarajevo, Bosnia & Herceg, [Putnik, K.] North Estonia Med Ctr, Tallinn, Estonia, [Weinlich, G.] Med Univ Innsbruck, Dept Dermatol & Venerol & Allergy, Innsbruck, Austria, [Todorovic, V.] Clin Oncol & Radiotherapy, Podgorica, Montenegro, [Kirov, K.] Natl Canc Ctr, Clin Oncodermatol, Sofia, Bulgaria, [Ocvirk, J.] Inst Oncol Ljubljana, Ljubljana, Slovenia, [Zhukavets, A.] NN Alexandrov Natl Canc Ctr Belarus NCCB, Minsk, BELARUS, [Kukushkina, M.] Natl Canc Inst, Kiev, Ukraine, [De La Cruz Merino, L.] Hosp Univ Virgen Macarena, Dept Clin Oncol, Seville, Spain, [Ymeri, A.] Univ Hosp Mother Theresa, Tirana, Albania, [Risteski, M.] Univ Clin Radiotherapy & Oncol, Skopje, Macedonia, [Garbe, C.] Eberhard Karls Univ Tubingen, Dept Dermatol, Ctr Dermatooncol, Tubingen, Germany, Kandolf Sekulovic, L., Peris, K., Hauschild, A., Stratigos, A., Grob, J. -J., Nathan, P., Dummer, R., Forsea, A. -M., Hoeller, C., Gogas, H., Demidov, L., Lebbe, C., Blank, C., Olah, J., Bastholt, L., Herceg, D., Neyns, B., Vieira, R., Hansson, J., Rutkowski, P., Krajsova, I., Bylaite-Bucinskiene, M., Zalaudek, I., Maric-Brozic, J., Babovic, N., Banjin, M., Putnik, K., Weinlich, G., Todorovic, V., Kirov, K., Ocvirk, J., Zhukavets, A., Kukushkina, M., De La Cruz Merino, L., Ymeri, A., Risteski, M., and Garbe, C.

Subjects
Human development index, Male, Cancer Research, Skin Neoplasms, Survival, medicine.medical_treatment, Access, Health expenditure per capita, Immunooncology, Innovative medicines, Metastatic melanoma, Targeted therapy, Treatment, Acrylonitrile, Aniline Compounds, Antibodies, Monoclonal, Humanized, Europe, Female, Health Services Accessibility, Healthcare Disparities, Humans, Immunotherapy, Melanoma, Programmed Cell Death 1 Receptor, Proto-Oncogene Proteins B-raf, Reimbursement Mechanisms, Therapies, Investigational, Oncology, Investigational, Reimbursement Mechanism, Melanoma/economics, Disparities, Immuno oncology, Medicines, 0302 clinical medicine, Diagnosis, Health care, Monoclonal, 030212 general & internal medicine, Healthcare Disparities/economics, Acce, Acrylonitrile/analogs & derivatives, Humanized, Proto-Oncogene Proteins B-raf/antagonists & inhibitors, Reimbursement, Programmed Cell Death 1 Receptor/antagonists & inhibitors, Aniline Compound, Healthcare Disparitie, Health Services Accessibility/economics, 030220 oncology & carcinogenesis, Targeted therapy Health, Innovative medicine, Health-care, Settore MED/35 - MALATTIE CUTANEE E VENEREE, Treatment Immunooncology, Human, medicine.medical_specialty, Reimbursement Mechanisms/statistics & numerical data, Union, Antibodies, Europe/epidemiology, Malignant-melanoma, 03 medical and health sciences, Pharmacotherapy, Internal medicine, medicine, Skin Neoplasm, Human Development Index, Mortality, Therapies, Investigational/economics, Skin Neoplasms/economics, Health policy, business.industry, Cancer, medicine.disease, access, innovative medicines, metastatic melanoma, treatment, immunooncologytargeted therapyhealth expenditure per capita, human development index, Surgery, Immunotherapy/economics, Therapies, Aniline Compounds/economics, Skin cancer, business, Cancer incidence, Antibodies, Monoclonal, Humanized/economics
Abstract

Background. Despite the efficacy of innovative treatments for metastatic melanoma, their high costs has led to disparities in cancer care among different European countries. We analysed the availability of these innovative therapies in Europeand estimated the number of patients without access to first-line recommended treatment per current guidelines of professional entities such as the European Society for Medical Oncology (ESMO), the European Organisation for Research and Treatment of Cancer (EORTC), the European Association of Dermato-Oncology (EADO), and European Dermatology Forum (EDF). Materials and methods Web-based online survey was conducted in 30 European countries with questions about the treatment schedules from 1st May 2015 to 1st May 2016: number of metastatic melanoma patients, registration and reimbursement of innovative medicines (updated data, as of 1st October 2016), percentage of patients treated and availability of clinical studies and compassionate-use programmes. Results The recommended BRAF inhibitor (BRAFi)+MEK inhibitor (MEKi) combination was both registered and fully reimbursed in 9/30 (30%) countries, and in 13/30 (43%) (all from Eastern Europe) not reimbursed. First-line immunotherapy with anti-PD1 antibodies was registered and fully reimbursed in 14/30 (47%) countries, while in 13/30 (43%) (all from Eastern Europe) not reimbursed. It was estimated that in Europe 19,600 patients with metastatic melanoma are treated, and 5238 (27%) do not have access to recommended first-line therapy. Significant correlation was found between human development index (HDI, UNDP report 2015), (r=0.662; p Previous article in issue

Published
2017
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22. Towards personalized therapy for multiple sclerosis: prediction of individual treatment response

Author

Suzanne Hodgkinson, Patrizia Sola, Jose Luis Sanchez-Menoyo, Mark Slee, Vahid Shaygannejad, Alexandre Prat, Jeannette Lechner-Scott, Lukas Sobisek, Raymond Hupperts, Vincent Van Pesch, Cristina Ramo-Tello, Csilla Rozsa, Guillermo Izquierdo, Helmut Butzkueven, Fraser Moore, Pamela A. McCombe, Maria Laura Saladino, Murat Terzi, Vilija Jokubaitis, Cavit Boz, Eugenio Pucci, Raed Alroughani, Shlomo Flechter, Pierre Grammond, Roberto Bergamaschi, G. Iuliano, Daniele Spitaleri, Francois Grand'Maison, Ali Manouchehrinia, Pierre Duquette, Tomas Kalincik, Marc Girard, Radek Ampapa, Michael Barnett, Jan Hillert, Freek Verheul, Maria Trojano, Franco Granella, Edgardo Cristiano, Maria Pia Amato, Dana Horakova, Alessandra Lugaresi, Celia Oreja-Guevara, Steve Vucic, Eva Havrdova, Tim Spelman, Javier Olascoaga, Kalincik, Toma, Manouchehrinia, Ali, Sobisek, Luka, Jokubaitis, Vilija, Spelman, Tim, Horakova, Dana, Havrdova, Eva, Trojano, Maria, Izquierdo, Guillermo, Lugaresi, Alessandra, Girard, Marc, Prat, Alexandre, Duquette, Pierre, Grammond, Pierre, Sola, Patrizia, Hupperts, Raymond, Grand'Maison, Francoi, Pucci, Eugenio, Boz, Cavit, Alroughani, Raed, Van Pesch, Vincent, Lechner-scott, Jeannette, Terzi, Murat, Bergamaschi, Roberto, Iuliano, Gerardo, Granella, Franco, Spitaleri, Daniele, Shaygannejad, Vahid, Oreja-guevara, Celia, Slee, Mark, Ampapa, Radek, Verheul, Freek, Mccombe, Pamela, Olascoaga, Javier, Amato, Maria Pia, Vucic, Steve, Hodgkinson, Suzanne, Ramo-tello, Cristina, Flechter, Shlomo, Cristiano, Edgardo, Rozsa, Csilla, Moore, Fraser, Sanchez-menoyo, Jose Lui, Saladino, Maria Laura, Barnett, Michael, Hillert, Jan, Butzkueven, Helmut, DIPARTIMENTO DI SCIENZE BIOMEDICHE E NEUROMOTORIE, OMÜ, [Kalincik, Tomas] Univ Melbourne, CORE, Dept Med, 300 Grattan St, Melbourne, Vic 3050, Australia, [Kalincik, Tomas] Royal Melbourne Hosp, Dept Neurol, 300 Grattan St, Melbourne, Vic 3050, Australia, [Jokubaitis, Vilija] Royal Melbourne Hosp, Dept Neurol, 300 Grattan St, Melbourne, Vic 3050, Australia, [Spelman, Tim] Royal Melbourne Hosp, Dept Neurol, 300 Grattan St, Melbourne, Vic 3050, Australia, [Manouchehrinia, Ali] Karolinska Inst, Dept Clin Neurosci, SE-17177 Stockholm, Sweden, [Sobisek, Lukas] Gen Univ Hosp, Dept Neurol, Katerinska 30, Prague 12808, Czech Republic, [Horakova, Dana] Gen Univ Hosp, Dept Neurol, Katerinska 30, Prague 12808, Czech Republic, [Havrdova, Eva] Gen Univ Hosp, Dept Neurol, Katerinska 30, Prague 12808, Czech Republic, [Sobisek, Lukas] Gen Univ Hosp, Ctr Clin Neurosci, Katerinska 30, Prague 12808, Czech Republic, [Horakova, Dana] Gen Univ Hosp, Ctr Clin Neurosci, Katerinska 30, Prague 12808, Czech Republic, [Havrdova, Eva] Gen Univ Hosp, Ctr Clin Neurosci, Katerinska 30, Prague 12808, Czech Republic, [Sobisek, Lukas] Charles Univ Prague, Katerinska 30, Prague 12808, Czech Republic, [Horakova, Dana] Charles Univ Prague, Katerinska 30, Prague 12808, Czech Republic, [Havrdova, Eva] Charles Univ Prague, Katerinska 30, Prague 12808, Czech Republic, [Sobisek, Lukas] Univ Econ Prague, Dept Stat & Probabil, Winston Churchill Sq 1938-4, Prague 13067, Czech Republic, [Jokubaitis, Vilija] Univ Melbourne, Dept Med, 300 Grattan St, Melbourne, Vic 3050, Australia, [Spelman, Tim] Univ Melbourne, Dept Med, 300 Grattan St, Melbourne, Vic 3050, Australia, [Trojano, Maria] Univ Bari, Via Calefati 53, I-70122 Bari, Italy, [Izquierdo, Guillermo] Hosp Univ Virgen Macarena, Amador De Los Rios 48-50 4a, Seville 41003, Spain, [Lugaresi, Alessandra] Univ G DAnnunzio, Dept Neurosci Imaging & Clin Sci, Via Vestini, I-66100 Chieti, Italy, [Lugaresi, Alessandra] Univ Bologna, Dept Biomed & Neuromotor Sci, Via Vestini, I-66100 Bologna, Italy, [Girard, Marc] Hop Notre Dame De Bon Secours, 1560 Sherbrooke East, Montreal, PQ H2L 4M1, Canada, [Prat, Alexandre] Hop Notre Dame De Bon Secours, 1560 Sherbrooke East, Montreal, PQ H2L 4M1, Canada, [Duquette, Pierre] Hop Notre Dame De Bon Secours, 1560 Sherbrooke East, Montreal, PQ H2L 4M1, Canada, [Girard, Marc] CHUM, Montreal, PQ, Canada, [Prat, Alexandre] CHUM, Montreal, PQ, Canada, [Duquette, Pierre] CHUM, Montreal, PQ, Canada, [Girard, Marc] Univ Montreal, Montreal, PQ, Canada, [Prat, Alexandre] Univ Montreal, Montreal, PQ, Canada, [Duquette, Pierre] Univ Montreal, Montreal, PQ, Canada, [Grammond, Pierre] Univ Montreal, Montreal, PQ, Canada, [Grammond, Pierre] Ctr Readaptat Deficience Phys Chaudiere Appalache, 9500 Blvd Ctr Hosp, Levis, AB G6X 0A1, Canada, [Sola, Patrizia] Nuovo Osped Civile St Agostino Estense, Via Giardini 1355, I-41100 Modena, Italy, [Hupperts, Raymond] Zuyderland Ziekenhuis, Walramstr 23, NL-6131 BK Sittard, Netherlands, [Grand'Maison, Francois] Neuro Rive Sud, 4896 Boul Taschereau,Suite 250, Greenfield Pk, PQ J4V 2J2, Canada, [Pucci, Eugenio] Azienda Sanitaria Unica Reg Marche AV3, Via Santa Lucia 2, I-62100 Macerata, Italy, [Boz, Cavit] Karadeniz Tech Univ, Farabi Hosp, Med Fac, TR-61080 Trabzon, Turkey, [Alroughani, Raed] Amiri Hosp, POB 1661, Kuwait 73767, Kuwait, [Van Pesch, Vincent] Clin Univ St Luc, Ave Hippocrate,10 UCL10-80, BXL-1200 Brussels, Belgium, [Lechner-Scott, Jeannette] Univ Newcastle, Lookout Rd, Newcastle, NSW 2305, Australia, [Terzi, Murat] Ondokuz Mayis Univ, Fac Med, TR-55160 Kurupelit, Turkey, [Bergamaschi, Roberto] C Mondino Natl Neurol Inst, Via Mondino 2, I-27100 Pavia, Italy, [Iuliano, Gerardo] Osped Riuniti Salerno, Via S Leonardo, I-84100 Salerno, Italy, [Granella, Franco] Univ Parma, Via Gramsci 14, I-43100 Parma, Italy, [Spitaleri, Daniele] Azienda Osped Rilievo Nazl San Giuseppe Moscati A, I-83100 Avellino, Italy, [Shaygannejad, Vahid] Isfahan Univ Med Sci, Soffeh St, Esfahan 81744, Iran, [Oreja-Guevara, Celia] Hosp Univ La Paz, Paseo Castellana 261, Madrid 28050, Spain, [Slee, Mark] Flinders Med Ctr, Flinders Dr, Adelaide, SA 5042, Australia, [Ampapa, Radek] Nemocnice Jihlava, Vrchlickeho 59, Jihlava 58633, Czech Republic, [Verheul, Freek] Groene Hart Ziekenhuis, Bleulandweg 10, NL-2800 BB Gouda, Netherlands, [McCombe, Pamela] Royal Brisbane & Womens Hosp, 33 North St, Spring Hill, Qld 4000, Australia, [Olascoaga, Javier] Hosp Donostia, Paseo Begiristain, San Sebastian 20014, Spain, [Amato, Maria Pia] Univ Florence, Viale Morgagni 85, I-50134 Florence, Italy, [Vucic, Steve] Westmead Hosp, Hawkesbury Rd, Sydney, NSW 2145, Australia, [Hodgkinson, Suzanne] Liverpool Hosp, Elizabeth St,21, Liverpool, SA, Australia, [Ramo-Tello, Cristina] Hosp Germans Trias i Pujol, Crtra Canyet S-N, Badalona 8916, Spain, [Flechter, Shlomo] Assaf Harofeh Med Ctr, IL-70100 Zerifin, Israel, [Cristiano, Edgardo] Hosp Italiano Buenos Aires, Guise 1870, RA-1425 Buenos Aires, DF, Argentina, [Rozsa, Csilla] Jahn Ferenc Teaching Hosp, Koves 1, H-1101 Budapest, Hungary, [Moore, Fraser] Jewish Gen Hosp, 3755 Cote St Catherine, Montreal, PQ J7A 4T8, Canada, [Luis Sanchez-Menoyo, Jose] Hosp Galdakao Usansolo, Barrio Labeaga S-N, Galdakao 48660, Spain, [Laura Saladino, Maria] INEBA Inst Neurosci Buenos Aires, Guardia Vieja 4435,C1192AAW, Buenos Aires, DF, Argentina, [Hillert, Jan] Univ Sydney, Brain & Mind Ctr, 100 Mallett, Camperdown, NSW 2050, Australia, [Butzkueven, Helmut] Monash Univ, Box Hill Hosp, Dept Neurol, Melbourne, Vic, Australia, National Health and Medical Research Council, National Health and Medical Research Council (centre for research excellence), University of Melbourne (Faculty of Medicine, Dentistry and Health Sciences research fellowship), Biogen, Novartis, Merck, Roche, Teva, Sanofi Genzyme, Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), and RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience

Subjects
Male, 0301 basic medicine, relapses, Databases, Factual, Failure, disability, multiple sclerosis, precision medicine, prediction, Disability Evaluation, Glatiramer acetate, 0302 clinical medicine, Natalizumab, Recurrence, Risk Factors, Medicine, Relapse, Progression, Precision medicine, Switch, Prognosis, Clinical Trial, Fingolimod, Multicenter Study, Treatment Outcome, Cohort, Disease Progression, Female, Algorithms, Immunosuppressive Agents, medicine.drug, Cohort study, Adult, Registry, medicine.medical_specialty, Multiple Sclerosis, Interferon-beta therapy, External validity, Disability, Multiple sclerosis, Prediction, Relapses, Neurology (clinical), Databases, Young Adult, 03 medical and health sciences, Internal medicine, Journal Article, Humans, Multiple sclerosi, Internal validity, Factual, Disease burden, Demography, business.industry, Prognostic-factors, Reproducibility of Results, Discontinuation, 030104 developmental biology, Physical therapy, business, 030217 neurology & neurosurgery, Forecasting
Abstract

none 47 si Timely initiation of effective therapy is crucial for preventing disability in multiple sclerosis; however, treatment response varies greatly among patients. Comprehensive predictive models of individual treatment response are lacking. Our aims were: (i) to develop predictive algorithms for individual treatment response using demographic, clinical and paraclinical predictors in patients with multiple sclerosis; and (ii) to evaluate accuracy, and internal and external validity of these algorithms. This study evaluated 27 demographic, clinical and paraclinical predictors of individual response to seven disease-modifying therapies in MSBase, a large global cohort study. Treatment response was analysed separately for disability progression, disability regression, relapse frequency, conversion to secondary progressive disease, change in the cumulative disease burden, and the probability of treatment discontinuation. Multivariable survival and generalized linear models were used, together with the principal component analysis to reduce model dimensionality and prevent overparameterization. Accuracy of the individual prediction was tested and its internal validity was evaluated in a separate, non-overlapping cohort. External validity was evaluated in a geographically distinct cohort, the Swedish Multiple Sclerosis Registry. In the training cohort (n = 8513), the most prominent modifiers of treatment response comprised age, disease duration, disease course, previous relapse activity, disability, predominant relapse phenotype and previous therapy. Importantly, the magnitude and direction of the associations varied among therapies and disease outcomes. Higher probability of disability progression during treatment with injectable therapies was predominantly associated with a greater disability at treatment start and the previous therapy. For fingolimod, natalizumab or mitoxantrone, it was mainly associated with lower pretreatment relapse activity. The probability of disability regression was predominantly associated with pre-baseline disability, therapy and relapse activity. Relapse incidence was associated with pretreatment relapse activity, age and relapsing disease course, with the strength of these associations varying among therapies. Accuracy and internal validity (n = 1196) of the resulting predictive models was high (480%) for relapse incidence during the first year and for disability outcomes, moderate for relapse incidence in Years 2-4 and for the change in the cumulative disease burden, and low for conversion to secondary progressive disease and treatment discontinuation. External validation showed similar results, demonstrating high external validity for disability and relapse outcomes, moderate external validity for cumulative disease burden and low external validity for conversion to secondary progressive disease and treatment discontinuation. We conclude that demographic, clinical and paraclinical information helps predict individual response to disease-modifying therapies at the time of their commencement. none Kalincik, Tomas; Manouchehrinia, Ali; Sobisek, Lukas; Jokubaitis, Vilija; Spelman, Tim; Horakova, Dana; Havrdova, Eva; Trojano, Maria; Izquierdo, Guillermo; Lugaresi, Alessandra; Girard, Marc; Prat, Alexandre; Duquette, Pierre; Grammond, Pierre; Sola, Patrizia; Hupperts, Raymond; Grand'Maison, Francois; Pucci, Eugenio; Boz, Cavit; Alroughani, Raed; Van Pesch, Vincent; Lechner-scott, Jeannette; Terzi, Murat; Bergamaschi, Roberto; Iuliano, Gerardo; Granella, Franco; Spitaleri, Daniele; Shaygannejad, Vahid; Oreja-guevara, Celia; Slee, Mark; Ampapa, Radek; Verheul, Freek; Mccombe, Pamela; Olascoaga, Javier; Amato, Maria Pia; Vucic, Steve; Hodgkinson, Suzanne; Ramo-tello, Cristina; Flechter, Shlomo; Cristiano, Edgardo; Rozsa, Csilla; Moore, Fraser; Sanchez-menoyo, Jose Luis; Saladino, Maria Laura; Barnett, Michael; Hillert, Jan; Butzkueven, Helmut Kalincik, Tomas; Manouchehrinia, Ali; Sobisek, Lukas; Jokubaitis, Vilija; Spelman, Tim; Horakova, Dana; Havrdova, Eva; Trojano, Maria; Izquierdo, Guillermo; Lugaresi, Alessandra; Girard, Marc; Prat, Alexandre; Duquette, Pierre; Grammond, Pierre; Sola, Patrizia; Hupperts, Raymond; Grand'Maison, Francois; Pucci, Eugenio; Boz, Cavit; Alroughani, Raed; Van Pesch, Vincent; Lechner-scott, Jeannette; Terzi, Murat; Bergamaschi, Roberto; Iuliano, Gerardo; Granella, Franco; Spitaleri, Daniele; Shaygannejad, Vahid; Oreja-guevara, Celia; Slee, Mark; Ampapa, Radek; Verheul, Freek; Mccombe, Pamela; Olascoaga, Javier; Amato, Maria Pia; Vucic, Steve; Hodgkinson, Suzanne; Ramo-tello, Cristina; Flechter, Shlomo; Cristiano, Edgardo; Rozsa, Csilla; Moore, Fraser; Sanchez-menoyo, Jose Luis; Saladino, Maria Laura; Barnett, Michael; Hillert, Jan; Butzkueven, Helmut

Published
2017

23. AKT2 suppresses pro-survival autophagy triggered by DNA double-strand breaks in colorectal cancer cells

Author

Jörg Fahrer, Teresa Frisan, Bernd Kaina, Mahmoud Toulany, Carina Neitzel, Marc Audebert, Nina Seiwert, Svenja Stroh, Department of Toxicology, University of Cagliari, Department of Cell and Molecular Biology, Karolinska Institutet [Stockholm], ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Department of Radiation Oncology, Division of Radiobiology and Molecular Environmental Research, University of Tuebingen, German Cancer Consortium, Johannes Gutenberg - Universität Mainz (JGU), Justus-Liebig-Universität Gießen (JLU), Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden, Partenaires INRAE, Métabolisme et Xénobiotiques (ToxAlim-MeX), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, and Fahrer, Jörg

Subjects
0301 basic medicine, Cancer Research, Programmed cell death, autophagy, appareil intestinal, DNA damage, [SDV]Life Sciences [q-bio], Immunology, ATG5, Bacterial Toxins, Ataxia Telangiectasia Mutated Proteins, autophagie, Biology, Transfection, human health, akt2, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Downregulation and upregulation, cellule intestinale, Cell Line, Tumor, Humans, DNA Breaks, Double-Stranded, Protein kinase B, ComputingMilieux_MISCELLANEOUS, différenciation cellulaire, Autophagy, Cell Biology, santé humaine, HCT116 Cells, 3. Good health, Cell biology, 030104 developmental biology, Apoptosis, cancer colorectal, 030220 oncology & carcinogenesis, Gene Knockdown Techniques, Cancer research, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Original Article, Signal transduction, Tumor Suppressor Protein p53, Colorectal Neoplasms, colorectal neoplasm, Proto-Oncogene Proteins c-akt, Signal Transduction
Abstract

DNA double-strand breaks (DSBs) are critical DNA lesions, which threaten genome stability and cell survival. DSBs are directly induced by ionizing radiation (IR) and radiomimetic agents, including the cytolethal distending toxin (CDT). This bacterial genotoxin harbors a unique DNase-I-like endonuclease activity. Here we studied the role of DSBs induced by CDT and IR as a trigger of autophagy, which is a cellular degradation process involved in cell homeostasis, genome protection and cancer. The regulatory mechanisms of DSB-induced autophagy were analyzed, focusing on the ATM-p53-mediated DNA damage response and AKT signaling in colorectal cancer cells. We show that treatment of cells with CDT or IR increased the levels of the autophagy marker LC3B-II. Consistently, an enhanced formation of autophagosomes and a decrease of the autophagy substrate p62 were observed. Both CDT and IR concomitantly suppressed mTOR signaling and stimulated the autophagic flux. DSBs were demonstrated as the primary trigger of autophagy using a DNase I-defective CDT mutant, which neither induced DSBs nor autophagy. Genetic abrogation of p53 and inhibition of ATM signaling impaired the autophagic flux as revealed by LC3B-II accumulation and reduced formation of autophagic vesicles. Blocking of DSB-induced apoptotic cell death by the pan-caspase inhibitor Z-VAD stimulated autophagy. In line with this, pharmacological inhibition of autophagy increased cell death, while ATG5 knockdown did not affect cell death after DSB induction. Interestingly, both IR and CDT caused AKT activation, which repressed DSB-triggered autophagy independent of the cellular DNA-PK status. Further knockdown and pharmacological inhibitor experiments provided evidence that the negative autophagy regulation was largely attributable to AKT2. Finally, we show that upregulation of CDT-induced autophagy upon AKT inhibition resulted in lower apoptosis and increased cell viability. Collectively, the findings demonstrate that DSBs trigger pro-survival autophagy in an ATM- and p53-dependent manner, which is curtailed by AKT2 signaling.

Published
2017
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24. Meal patterns across ten European countries - results from the European Prospective Investigation into Cancer and Nutrition (EPIC) calibration study

Author

E Huseinovic, A Winkvist, N Slimani, MK Park, H Freisling, H Boeing, G Buckland, L Schwingshackl, E Weiderpass, AL Rostgaard-Hansen, A Tjønneland, A Affret, MC Boutron-Ruault, G Fagherazzi, V Katzke, T Kühn, A Naska, P Orfanos, A Trichopoulou, V Pala, D Palli, F Ricceri, M Santucci de Magistris, R Tumino, D Engeset, T Enget, G Skeie, A Barricarte, CB Bonet, MD Chirlaque, P Amiano, JR Quirós, MJ Sánchez, JA Dias, I Drake, M Wennberg, JMA Boer, MC Ocké, WMM Verschuren, C Lassale, A Perez-Cornago, E Riboli, H Ward, H Bertéus Forslund, [Huseinovic, E.] Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Box 459, SE-40530 Gothenburg, Sweden, [Winkvist, A.] Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Box 459, SE-40530 Gothenburg, Sweden, [Forslund, H. Berteus] Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Box 459, SE-40530 Gothenburg, Sweden, [Winkvist, A.] Umea Univ, Nutr Res, Dept Publ Hlth & Clin Med, Umea, Sweden, [Wennberg, M.] Umea Univ, Nutr Res, Dept Publ Hlth & Clin Med, Umea, Sweden, [Slimani, N.] Int Agcy Res Canc, Dietary Exposure Assessment Grp, Lyon, France, [Park, M. K.] Int Agcy Res Canc, Dietary Exposure Assessment Grp, Lyon, France, [Freisling, H.] Int Agcy Res Canc, Dietary Exposure Assessment Grp, Lyon, France, [Boeing, H.] German Inst Human Nutr, Dept Epidemiol, Nuthetal, Germany, [Schwingshackl, L.] German Inst Human Nutr, Dept Epidemiol, Nuthetal, Germany, [Buckland, G.] Catalan Inst Oncol ICO IDIBELL, Unit Nutr & Canc, Canc Epidemiol Res Programme, Barcelona, Spain, [Bonet, C. B.] Catalan Inst Oncol ICO IDIBELL, Unit Nutr & Canc, Canc Epidemiol Res Programme, Barcelona, Spain, [Weiderpass, E.] Univ Tromso, Arctic Univ Norway, Dept Community Med, Fac Hlth Sci, Tromso, Norway, [Enget, T.] Univ Tromso, Arctic Univ Norway, Dept Community Med, Fac Hlth Sci, Tromso, Norway, [Skeie, G.] Univ Tromso, Arctic Univ Norway, Dept Community Med, Fac Hlth Sci, Tromso, Norway, [Weiderpass, E.] Inst Populat Based Canc Res, Canc Registry Norway, Dept Res, Oslo, Norway, [Weiderpass, E.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden, [Weiderpass, E.] Folkhalsan Res Ctr, Genet Epidemiol Grp, Helsinki, Finland, [Rostgaard-Hansen, A. L.] Danish Canc Soc Res Ctr, Copenhagen, Denmark, [Tjonneland, A.] Danish Canc Soc Res Ctr, Copenhagen, Denmark, [Affret, A.] Univ Paris Sud, Univ Paris Saclay, UVSQ, CESP,INSERM, Villejuif, France, [Boutron-Ruault, M. C.] Univ Paris Sud, Univ Paris Saclay, UVSQ, CESP,INSERM, Villejuif, France, [Fagherazzi, G.] Univ Paris Sud, Univ Paris Saclay, UVSQ, CESP,INSERM, Villejuif, France, [Affret, A.] Gustave Roussy, Villejuif, France, [Boutron-Ruault, M. C.] Gustave Roussy, Villejuif, France, [Fagherazzi, G.] Gustave Roussy, Villejuif, France, [Katzke, V.] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany, [Kuehn, T.] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany, [Naska, A.] Hellen Hlth Fdn, Athens, Greece, [Orfanos, P.] Hellen Hlth Fdn, Athens, Greece, [Trichopoulou, A.] Hellen Hlth Fdn, Athens, Greece, [Naska, A.] Univ Athens, WHO Collaborating Ctr Nutr & Hlth, Unit Nutr Epidemiol & Nutr Publ Hlth, Dept Hyg Epidemiol & Med Stat,Med Sch, Athens, Greece, [Orfanos, P.] Univ Athens, WHO Collaborating Ctr Nutr & Hlth, Unit Nutr Epidemiol & Nutr Publ Hlth, Dept Hyg Epidemiol & Med Stat,Med Sch, Athens, Greece, [Trichopoulou, A.] Univ Athens, WHO Collaborating Ctr Nutr & Hlth, Unit Nutr Epidemiol & Nutr Publ Hlth, Dept Hyg Epidemiol & Med Stat,Med Sch, Athens, Greece, [Pala, V.] Fdn IRCCS Ist Nazl Tumori, Dept Prevent & Predict Med, Epidemiol & Prevent Unit, Milan, Italy, [Palli, D.] Canc Res & Prevent Inst ISPO, Mol & Nutr Epidemiol Unit, Florence, Italy, [Ricceri, F.] Reg Hlth Serv ASL TO3, Unit Epidemiol, Grugliasco, TO, Italy, [Ricceri, F.] Univ Turin, Dept Med Sci, Unit Canc Epidemiol, Turin, Italy, [de Magistris, M. Santucci] AOU Federico II, Naples, Italy, [Tumino, R.] ASP Ragusa, Civ MP Arezzo Hosp, Canc Registry & Histopathol Unit, Ragusa, Italy, [Engeset, D.] Norwegian Food Safety Author, Head Off, Oslo, Norway, [Barricarte, A.] Navarra Publ Hlth Inst, Pamplona, Spain, [Barricarte, A.] Navarra Inst Hlth Res IdiSNA, Pamplona, Spain, [Barricarte, A.] CIBER Epidemiol & Publ Hlth CIBERESP, Madrid, Spain, [Chirlaque, M. D.] CIBER Epidemiol & Publ Hlth CIBERESP, Madrid, Spain, [Amiano, P.] CIBER Epidemiol & Publ Hlth CIBERESP, Madrid, Spain, [Sanchez, M. J.] CIBER Epidemiol & Publ Hlth CIBERESP, Madrid, Spain, [Chirlaque, M. D.] IMIB Arrixaca, Reg Hlth Council, Dept Epidemiol, Murcia, Spain, [Chirlaque, M. D.] Univ Murcia, Dept Hlth & Social Sci, Murcia, Spain, [Amiano, P.] BioDonostia Res Inst, Publ Hlth Div Gipuzkoa, San Sebastian, Spain, [Quiros, J. R.] Publ Hlth Directorate, Asturias, Spain, [Sanchez, M. J.] Univ Granada, Hosp Univ Granada, Inst Invest Biosanitaria Ibs GRANADA, Escuela Andaluza Salud Publ, Granada, Spain, [Dias, J. A.] Lund Univ, Dept Clin Sci Malmo, Lund, Sweden, [Drake, I.] Lund Univ, Dept Clin Sci Malmo, Lund, Sweden, [Boer, J. M. A.] Natl Inst Publ Hlth & Environm RIVM, Ctr Nutr Prevent & Hlth Serv, Bilthoven, Netherlands, [Ocke, M. C.] Natl Inst Publ Hlth & Environm RIVM, Ctr Nutr Prevent & Hlth Serv, Bilthoven, Netherlands, [Verschuren, W. M. M.] Natl Inst Publ Hlth & Environm RIVM, Ctr Nutr Prevent & Hlth Serv, Bilthoven, Netherlands, [Verschuren, W. M. M.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands, [Lassale, C.] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England, [Riboli, E.] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England, [Ward, H.] Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England, [Perez-Cornago, A.] Univ Oxford, Nuffield Dept Populat Hlth, Canc Epidemiol Unit, Oxford, England, European Commission (DG-SANCO), International Agency for Research on Cancer, Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (INSERM) (France), German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, Federal Ministry of Education and Research (Germany), Hellenic Health Foundation (Greece), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands), Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway), Health Research Fund (FIS), Regional Governments of Andalucia, Asturias, Basque Country, Murcia, Navarra, ISCIII RETIC (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Skane and Vasterbotten (Sweden), Cancer Research UK, Medical Research Council, MRC, and National Institute for Health Research

Subjects
0301 basic medicine, Gerontology, Male, Cross-sectional study, Calibration (statistics), Medicine (miscellaneous), EPIC, VDP::Medical disciplines: 700::Health sciences: 800::Nutrition: 811, Intake occasion, Feeding behavior, Medicine, Prospective Studies, Dietary-intake, Prospective cohort study, Meals, Meal patterns, Nutrition and Dietetics, 11 Medical And Health Sciences, Middle Aged, Research Papers, Nutrient intake, European Prospective Investigation into Cancer and Nutrition, Europe, Snacking, Female, 24 h dietary recall, Energy intake, Intake frequency, Snacks, Standardization, Adult, Aged, Cross-Sectional Studies, Energy Intake, Humans, Diet, Diet Surveys, Feeding Behavior, Cutoff, Population, VDP::Medisinske Fag: 700::Helsefag: 800::Ernæring: 811, 03 medical and health sciences, Environmental health, 030109 nutrition & dietetics, Nutrition & Dietetics, business.industry, Public Health, Environmental and Occupational Health, Frequency, Overweight, Recalls, Weight-loss, Energy-intake, business
Abstract

ObjectiveTo characterize meal patterns across ten European countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) calibration study.DesignCross-sectional study utilizing dietary data collected through a standardized 24 h diet recall during 1995–2000. Eleven predefined intake occasions across a 24 h period were assessed during the interview. In the present descriptive report, meal patterns were analysed in terms of daily number of intake occasions, the proportion reporting each intake occasion and the energy contributions from each intake occasion.SettingTwenty-seven centres across ten European countries.SubjectsWomen (64 %) and men (36 %) aged 35–74 years (n 36 020).ResultsPronounced differences in meal patterns emerged both across centres within the same country and across different countries, with a trend for fewer intake occasions per day in Mediterranean countries compared with central and northern Europe. Differences were also found for daily energy intake provided by lunch, with 38–43 % for women and 41–45 % for men within Mediterranean countries compared with 16–27 % for women and 20–26 % for men in central and northern European countries. Likewise, a south–north gradient was found for daily energy intake from snacks, with 13–20 % (women) and 10–17 % (men) in Mediterranean countries compared with 24–34 % (women) and 23–35 % (men) in central/northern Europe.ConclusionsWe found distinct differences in meal patterns with marked diversity for intake frequency and lunch and snack consumption between Mediterranean and central/northern European countries. Monitoring of meal patterns across various cultures and populations could provide critical context to the research efforts to characterize relationships between dietary intake and health.

Published
2016

25. CYP1A1, GSTM1, and GSTT1 Polymorphisms, Smoking, and Lung Cancer Risk in a Pooled Analysis among Asian Populations

Author

Margie L. Clapper, Qing Lan, Pinpin Lin, Petcharin Srivatanakul, Chikako Kiyohara, Maria Li Lung, Haruhiko Sugimura, Jun Yokota, Shinkan Tokudome, Paola Pisani, Shen Min, Emanuela Taioli, Daehee Kang, Magnus Ingelman-Sundberg, Masko Ono-Kihara, Kyoung-Mu Lee, Loic Le Marchand, Adeline Seow, Hatice Pinarbasi, [Lee, Kyoung-Mu -- Kang, Daehee] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul 110799, South Korea -- [Kang, Daehee] Seoul Natl Univ, Canc Res Inst, Seoul 110799, South Korea -- [Clapper, Margie L.] Fox Chase Canc Ctr, Div Populat Sci, Philadelphia, PA 19111 USA -- [Ingelman-Sundberg, Magnus] Karolinska Inst, Dept Physiol Chem, S-10401 Stockholm, Sweden -- [Ono-Kihara, Masko] Kyoto Univ, Dept Global Hlth & Socioepidemiol, Sch Publ Hlth, Kyoto, Japan -- [Kiyohara, Chikako] Kyushu Univ, Grad Sch Med Sci, Fukuoka 812, Japan -- [Lee, Kyoung-Mu -- Min, Shen -- Lan, Qing] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA -- [Le Marchand, Loic] Univ Hawaii, Canc Res Ctr Hawaii, Honolulu, HI 96813 USA -- [Lin, Pinpin] Natl Hlth Res Inst, Zhunan, Taiwan -- [Lung, Maria Li] Hong Kong Univ Sci & Technol, Dept Biol, Kowloon, Hong Kong, Peoples R China -- [Lung, Maria Li] Hong Kong Univ Sci & Technol, Ctr Canc Res, Kowloon, Hong Kong, Peoples R China -- [Pinarbasi, Hatice] Cumhuriyet Univ, Dept Biochem, Fac Med, Sivas, Turkey -- [Pisani, Paola] Univ Oxford, Canc Epidemiol Unit, Oxford, England -- [Srivatanakul, Petcharin] Natl Canc Inst, Canc Control Unit, Bangkok, Thailand -- [Seow, Adeline] Natl Univ Singapore, Dept Community Occupat & Family Med, Singapore 117548, Singapore -- [Sugimura, Haruhiko] Hamamatsu Univ Sch Med, Dept Pathol, Shizuoka, Japan -- [Tokudome, Shinkan] Nagoya City Univ, Dept Hlth Promot & Prevent Med, Grad Sch Med Sci, Nagoya, Aichi, Japan -- [Yokota, Jun] Natl Canc Ctr, Res Inst, Div Biol, Tokyo 104, Japan -- [Taioli, Emanuela] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA, Lin, Pinpin -- 0000-0001-5459-907X, Lin, PinPin -- 0000-0001-5459-907X, Lung, Maria Li -- 0000-0003-2559-3626, and TOKUDOME, SHINKAN -- 0000-0001-7311-2458

Subjects
Male, Risk, Oncology, medicine.medical_specialty, Lung Neoplasms, Genotype, Epidemiology, Bioinformatics, Asian People, Internal medicine, Cytochrome P-450 CYP1A1, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Lung cancer, Aged, Glutathione Transferase, Aged, 80 and over, Chi-Square Distribution, Polymorphism, Genetic, business.industry, Smoking, Haplotype, Cancer, Environmental exposure, Odds ratio, Middle Aged, medicine.disease, Confidence interval, Logistic Models, Haplotypes, Female, business
Abstract

WOS: 000256012800016, PubMed ID: 18463401, evaluate the roles of CYP1A1 polymorphisms [Ile (462)Val and (TC)-C-6235 (MspI)] and deletion of GSTM1 and and GSTT1 in lung cancer development in Asian populations, a pooled analysis was conducted on 13 existing studies included in Genetic Susceptibility to Environmental Carcinogenesis database. This pooled analysis included 1,971 cases and 2,130 controls. Lung cancer risk was estimated as odds ratios (OR) and 95% confidence intervals (95% CD using unconditional logistic regression model adjusting for age, sex, and pack-year. The CYP1A1 C-6235 variant was associated with squamous cell lung cancer (TC versus TT: OR, 1.42; 95% CI, 0.96-2.09; CC versus TT: OR, 1.97; 95% CI, 1.26-3.07; P-trend = 0.003). In haplotype analysis, (462)Val-T-6235 and Ile-C haplotypes were associated with lung cancer risk with reference to the Ile-T haplotype (OR, 3.41; 95% CI, 1.78-6.53 and OR, 1.39; 95% CI, 1.12-1.71, respectively). The GSTM1-null genotype increased squamous cell lung cancer risk (OR, 1.36; 95% CI, 1.05-1.77). When the interaction was evaluated with smoking, increasing trend of lung cancer risk as pack-year increased was stronger among those with the CYP1A1 6235 TC/CC genotype compared with those with IT genotype (P-interaction = 0.001) and with the GSTM1-null genotype compared with the present type (Pinteraction 0.08, when no genotype effect with no exposure was assumed). These results suggest that genetic polymorphisms in CYP1A1 and GSTM1 are associated with lung cancer risk in Asian populations. However, further investigation is warranted considering the relatively small sample size when subgroup analyses were done and the lack of environmental exposure data other than smoking., NCI NIH HHS [2P50CA090440-06, P30CA047904-19S1]

Published
2008
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26. Structural insights into the DNA-binding specificity of E2F family transcription factors

Author

Nadejda Eremina, Bernhard Schmierer, Ekaterina Morgunova, Kashyap Dave, Yimeng Yin, Jussi Taipale, Lennart Nilsson, Arttu Jolma, Alexander Popov, Karolinska Inst, Dept Biosci & Nutr, SE-14183 Stockholm, Sweden, European Synchrotron Radiation Facility (ESRF), Stockholm Univ, Dept Biochem & Biophys, SE-10691 Stockholm, Sweden, Univ Helsinki, Genome Scale Biol Res Program, Fac Med, FI-00014 Helsinki, Finland, Research Programs Unit, Genome-Scale Biology (GSB) Research Program, and Jussi Taipale / Principal Investigator

Subjects
PROTEINS, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Biology, Molecular Dynamics Simulation, Crystallography, X-Ray, DNA-binding protein, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Protein structure, Species Specificity, Transcription (biology), Humans, NUCLEIC-ACIDS, OPTIMIZATION, E2F, Transcription factor, 030304 developmental biology, Genetics, SITES, 0303 health sciences, ROLES, Multidisciplinary, REPRESSION, RECOGNITION, General Chemistry, DNA, Cell biology, E2F Transcription Factors, Protein Structure, Tertiary, DNA-Binding Proteins, stomatognathic diseases, RESOLUTION, chemistry, 030220 oncology & carcinogenesis, Multigene Family, SIMULATION, FORCE-FIELD, 3111 Biomedicine, biological phenomena, cell phenomena, and immunity, Chromatin immunoprecipitation
Abstract

The mammalian cell cycle is controlled by the E2F family of transcription factors. Typical E2Fs bind to DNA as heterodimers with the related dimerization partner (DP) proteins, whereas the atypical E2Fs, E2F7 and E2F8 contain two DNA-binding domains (DBDs) and act as repressors. To understand the mechanism of repression, we have resolved the structure of E2F8 in complex with DNA at atomic resolution. We find that the first and second DBDs of E2F8 resemble the DBDs of typical E2F and DP proteins, respectively. Using molecular dynamics simulations, biochemical affinity measurements and chromatin immunoprecipitation, we further show that both atypical and typical E2Fs bind to similar DNA sequences in vitro and in vivo. Our results represent the first crystal structure of an E2F protein with two DBDs, and reveal the mechanism by which atypical E2Fs can repress canonical E2F target genes and exert their negative influence on cell cycle progression., The E2F family of transcription factors controls many important cellular processes. Here, the authors determine the structure of an atypical E2F that contains two DNA binding domains, and propose a mechanism of action for these atypical E2Fs.

Published
2015
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27. Stage at presentation of breast cancer in Luanda, Angola - a retrospective study

Author

Helga Freitas, Clara Castro, Lygia Vieira Lopes, Gonçalo Forjaz Lacerda, Elisabete Weiderpass, Salvador Pangui, Fernando Miguel, Adhemar Longatto-Filho, Lúcio Lara Santos, António Tavares, Universidade do Minho, Sagrada Esperanca Clin, Angolan Inst Canc Control, Minist Hlth, Azores Oncol Ctr, Univ Minho, Universidade Estadual Paulista (Unesp), CPOM, Canc Registry Norway, Arctic Univ Norway, Karolinska Inst, Samfundet Folkhalsan, ONCOCIR Educ & Care Oncol, and Portuguese Oncol Inst Porto

Subjects
Adult, Pediatrics, medicine.medical_specialty, Ciências da Saúde [Ciências Médicas], Ciências Médicas::Ciências da Saúde, Axillary lymph nodes, Breast Neoplasms, Disease, Metastasis, 03 medical and health sciences, Breast cancer, 0302 clinical medicine, medicine, Humans, 030212 general & internal medicine, Stage (cooking), 10. No inequality, Early Detection of Cancer, Aged, Neoplasm Staging, Retrospective Studies, Aged, 80 and over, Gynecology, Medical Audit, Science & Technology, Cancer prevention, business.industry, Health Policy, 1. No poverty, Cancer, Retrospective cohort study, Middle Aged, medicine.disease, 3. Good health, medicine.anatomical_structure, Angola, 030220 oncology & carcinogenesis, Africa, Clinical and pathological characterization, Female, Lymph Nodes, business, Research Article
Abstract

Background: It is expected that, by 2020, 15 million new cases of cancer will occur every year in the world, one million of them in Africa. Knowledge of cancer trends in African countries is far from adequate, and improvements in cancer prevention efforts are urgently needed. The aim of this study was to characterize breast cancer clinically and pathologically at presentation in Luanda, Angola; we additionally provide quality information that will be useful for breast cancer care planning in the country. Methods: Data on breast cancer cases were retrieved from the Angolan Institute of Cancer Control, from 2006 to 2014. For women diagnosed in 2009 (5-years of follow-up), demographic, clinical and pathological information, at presentation, was collected, namely age at diagnosis, parity, methods used for pathological diagnoses, tumor pathological characteristics, stage of disease and treatment. Descriptive statistics were performed. Results: The median age of women diagnosed with breast cancer in 2009 was 47 years old (range 25–89). The most frequent clinical presentation was breast swelling with axillary lymph nodes metastasis (44.9 %), followed by a mass larger than 5 cm (14.2 %) and lump (12.9 %). Invasive ductal carcinoma was the main histologic type (81.8 %). Only 10.1 % of cancer cases had a well differentiated histological grade. Cancers were diagnosed mostly at advanced stages (66.7 % in stage III and 11.1 % in stage IV). Discussion: In this study, breast cancer was diagnosed at a very advanced stage. Although it reports data from a single cancer center in Luanda, Angola it reinforces the need for early diagnosis and increasing awareness. According to the main challenges related to breast cancer diagnosis and treatment herein presented, we propose a realistic framework that would allow for the implementation of a breast cancer care program, built under a strong network based on cooperation, teaching, audit, good practices and the organization of health services. Conclusion: Angola needs urgently a program for early diagnosis of breast cancer., We thank Susana Santos for correction of the article in English language, and a Cancer Registry Staff from IACC, particularly Pedro Luis Hernandez Gonzalez, Paulo Ernesto Alves, Xacu Parica and Alberto Sivi Lutumba for their support in data acquisition. We also thank SEMED -Portugal in support for publication.

Published
2015
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28. Quality of care in European home care programs using the second generation interRAI Home Care Quality Indicators (HCQIs)

Author

Dinnus Frijters, Vjenka Garms-Homolová, Henriëtte G. van der Roest, Roberto Bernabei, Graziano Onder, Hein P.J. van Hout, John P. Hirdes, Eva Topinkova, Andrea D. Foebel, Palmi V. Jonsson, Harriet Finne-Soveri, General practice, EMGO - Quality of care, and [ 1 ] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden [ 2 ] Univ Cattolica Sacro Cuore, Dept Geriatr Neurosci & Orthoped, I-00168 Rome, Italy [ 3 ] Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Dept Gen Practice & Elderly Care Med, Amsterdam, Netherlands [ 4 ] Charles Univ Prague, Fac Med 1, Dept Geriatr, Prague, Czech Republic [ 5 ] Univ Appl Sci Technol & Econ, HTW Berlin, Berlin, Germany [ 6 ] Natl Inst Hlth & Welf, Helsinki, Finland [ 7 ] Univ Iceland, Fac Med, Dept Geriatr, Reykjavik, Iceland [ 8 ] Univ Waterloo, Sch Publ Hlth & Hlth Syst, Waterloo, ON N2L 3G1, Canada

Subjects
Gerontology, Male, Aging, Activities of daily living, Social quality, Quality Indicators, Health Care/standards, media_common.quotation_subject, Denmark, Psychological intervention, Quality indicators, Assessment, InterRAI, Home care, Cohort Studies, Quality of life (healthcare), Home Care Services/standards, Germany, Activities of Daily Living, Performance measurement, Ethnicity, Medicine, Humans, Quality (business), Geriatric Assessment, Finland, media_common, Aged, Czech Republic, Netherlands, Quality Indicators, Health Care, Aged, 80 and over, Aldraðir, business.industry, Settore MED/09 - MEDICINA INTERNA, Home Care Services, 3. Good health, Europe, Italy, Scale (social sciences), Models, Organizational, Cohort, Quality of Life, Female, Geriatrics and Gerontology, INGLESE, business, Cohort study, Research Article
Abstract

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. Evaluating the quality of care provided to older individuals is a key step to ensure that needs are being met and to target interventions to improve care. To this aim, interRAI's second-generation home care quality indicators (HCQIs) were developed in 2013. This study assesses the quality of home care services in six European countries using these HCQIs as well as the two derived summary scales. Data for this study were derived from the Aged in Home Care (AdHOC) study - a cohort study that examined different models of community care in European countries. The current study selected a sub-sample of the AdHOC cohort from six countries whose follow-up data were complete (Czech Republic, Denmark, Finland, Germany, Italy and the Netherlands). Data were collected from the interRAI Home Care instrument (RAI-HC) between 2000 and 2002. The 23 HCQIs of interest were determined according to previously established methodology, including risk adjustment. Two summary measures, the Clinical Balance Scale and Independence Quality Scale were also determined using established methodology. A total of 1,354 individuals from the AdHOC study were included in these analyses. Of the 23 HCQIs that were measured, the highest proportion of individuals experienced declines in Instrumental Activities of Daily Living (IADLs) (48.4 %). Of the clinical quality indicators, mood decline was the most prevalent (30.0 %), while no flu vaccination and being alone and distressed were the most prevalent procedural and social quality indicators, respectively (33.4 and 12.8 %). Scores on the two summary scales varied by country, but were concentrated around the median mark. The interRAI HCQIs can be used to determine the quality of home care services in Europe and identify areas for improvement. Our results suggest functional declines may prove the most beneficial targets for interventions. info:eu-repo/grantAgreement/EC/FP7/305912

Published
2015
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29. Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age

Author

Doris Lechner, Miriam Capri, Stefan Böhringer, Stefan Schreiber, Gonneke Willemsen, Paolo Garagnani, Irene Maeve Rea, Andres Metspalu, Palmi V. Jonsson, Thomas B. L. Kirkwood, Lene Christiansen, Fernando Rivadeneira, Giuseppina Rose, J. Wouter Jukema, Serena Dato, Owen A. Ross, Almut Nebel, Cornelia M. van Duijn, Gary Saunders, Bernard Jeune, David J. Stott, Jeanine J. Houwing-Duistermaat, A. Murphy, Anton J. M. de Craen, Friederike Flachsbart, Karen Andersen-Ranberg, Albert Hofman, Ian Ford, Ellen A. Nohr, Giuseppe Passarino, Krista Fischer, Elisa Cevenini, Carmen Martin-Ruiz, Jutta Gampe, Iris Postmus, Christopher P. Nelson, Stefano Salvioli, Alberto Montesanto, Mark Lathrop, Marianne Nygaard, Marie E. Breen, Jennifer Harrow, Hae-Won Uh, Erik B. van den Akker, Thorkild I. A. Sørensen, André G. Uitterlinden, Alexander Viktorin, Bastiaan T. Heijmans, Susan E. McNerlan, Quinta Helmer, Naveed Sattar, Claudio Franceschi, Eco J. C. de Geus, E. Mihailov, Jouke-Jan Hottenga, Qihua Tan, Kari Stefansson, Yoichiro Kamatani, Paolina Crocco, Henning Tiemeier, Stella Trompet, Patrik K. E. Magnusson, Marian Beekman, Riin Tamm, Amke Caliebe, Maris Alver, Femke-Anouska Heinsen, Pilar Galan, Daníel F. Guðbjartsson, Joris Deelen, Linda Broer, Ruud van der Breggen, Kristin L. Ayers, Anna M. Bennet, Dorret I. Boomsma, P. Eline Slagboom, Kaare Christensen, Diana van Heemst, Joanna Collerton, Karen Davies, Rudi G. J. Westendorp, Hélène Blanché, Lavinia Paternoster, Nilesh J. Samani, Hreinn Stefansson, Simon P. Mooijaart, Heather J. Cordell, Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), LeidenUniversity Medical Centre, Department of Epidemiology, The Netherlands Cancer Institute, Institute of Genetic Medicine, Newcastle University [Newcastle], National Institute of Public Health, University of Southern Denmark (SDU), Department of Clinical Genetics, Odense University Hospital, Fondation Jean Dausset - Centre d’Étude du Polymorphisme Humain, Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], University of Tartu, Institute of Molecular and Cell Biology, Department of Gerontology and Geriatrics, Leiden University Medical Center (LUMC), deCODE genetics [Reykjavik], Christian-Albrechts University of Kiel, University of Calabria, Delft University of Technology (TU Delft), Department of Cardiovascular Sciences, Université Catholique de Louvain = Catholic University of Louvain (UCL), University Hospitals Leicester, Genome Campus, The Wellcome Trust Sanger Institute [Cambridge], School of Medicine, Dentistry and Biomedical Sciences [Belfast], Queen's University [Belfast] (QUB), University of Iowa [Iowa City], DIMES: Department of Experimental, Diagnostic and Specialty Medicine, Bologna University Hospital, Institute for Ageing and Health, University of Glasgow, Max Planck Institute for Demographic Research (MPIDR), Max-Planck-Gesellschaft, Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), EMGO Institute for Health and Care Research, VU University Amsterdam Medical Center, Landspitali National University Hospital of Iceland, University of Iceland, McGill University = Université McGill [Montréal, Canada], Genome Quebec Innovation Centre, Institut de Génomique, Belfast Health and Social Care Trust, Estonian Biocentre, Partenaires INRAE, Aarhus University [Aarhus], School of Social and Community Medicine, Erasmus University Rotterdam, Mayo Clinic, BHF Glasgow Cardiovascular Research Centre, University Medical Center Schleswig-Holstein, Institute of Cardiovascular and Medical Sciences, Sophia Children's Hospital, Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Augustinus Foundation, Avera Institute for Human Genetics (AIHG), AXA Research Fund, Belfast City Hospital Trust Fund, Biobanking and Biomolecular Resources Research Infrastructure (BBMRI -NL) [184.021.007], Biotechnology and Biological Sciences Research Council (BBSRC), Bristol-Myers Squibb, Center for Inherited Disease Research (CIDR), Centre for Medical Systems Biology (CMSB), CERA Foundation, Commissariat a L'Energie Atomique (CEA)-Centre National de Genotypage (CNG), Danish Agency for Science, Technology and Innovation (DASTI)/The Danish Council for Independent Research (DCIR) [11-107308], Danish National Research Foundation (DNRF), Department of Health and Social Services (Northern Ireland), DFG-Cluster of Excellence 'Inflammation at Interfaces', Dunhill Medical Trust [R124/0509], Egmont Foundation, Estonian Science Foundation [7859], Estonian Government [SF0180142s08], European Research Council (ERC) [230374], European Science Foundation (ESF) [EU/QLRT-2001-01254], European Union [FP5-QLK6-CY-2001-00128, FP6-LIFESCIHEALTH-36894, FP6-LSH M-CT-2004-503270, FP7-HEALTH-2007-B-223004, FP7-HEALTH-F4-2007-201413, FP7-HEALTH-F4-2008-202047, FP7-HEALTH-2009-single-stage-242244, FP7-HEALTH-2010-two-stage-259679], Fondation Caisse d'Epargne Rhone-Alpes Lyon CERAL, Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health (NIMH) [MH081802], GenomEUtwin [EU/QLRT-2001-01254, QLG2-CT-2002-01254], Guy's & St Thomas' NHS Foundation Trust, Health Foundation, Heart and Lung foundation [20070481], Innovation-Oriented Research Program on Genomics (SenterNovem) [IGE05007], Institut National de la Recherche Agronomique (INRA), Institut National de la Sante et de la Recherche Medicale (INSERM), King's College London, Medical Research Council (MRC) [G0500997, G0601333], Ministere de l'Enseignement superieur et de la Recherche (MESR), National Institutes of Health (NIH)/National Institute of Aging (NIA) [P01AG08761, R01D0042157-01A, U01DK066134], National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre, NBIC BioAssist [NWO-NBIC/BioAssist/RK/2008.024], Netherlands Consortium for Healthy Ageing (NCHA) [050-060-810], Netherlands Genomics Initiative (NGI), Netherlands Heart Foundation (NHF) [2001 D 032], Netherlands Organization for Scientific Research (NWO, MagW/ZonMW) [904-61-090, 904-61-193, 480-04-004, 400-05-717, Spinozapremie 56-464-14192, 175.010.2005.011, 911-03-012, 985-10-002, Addiction-31160008, Middelg-root-911-09-032], Netspar - Living longer for a good health, NHS North of Tyne (Newcastle Primary Care Trust), Pharmacy Foundation, Regione Autonoma della Sardegna, Rutgers University Cell and DNA Repository [NIMH U24 MH068457-06], Swedish Research Council [M-2005-1112], Tampere University Hospital and Academy of Finland, Danish Interdisciplinary Research Council, Health Foundation (Helsefonden), Ministry for Higher Education, National Program for Research Infrastructure [09-063256], March of Dimes Birth Defects Foundation, Swedish Foundation for Strategic Research (SSF), Unilever Discover Colworth, Universite Paris 13, University of Tartu [SP1GVAR-ENG], Velux Foundation, VU University's Institute for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam (NCA), Wellcome Trust [084762, 085475, 087436], IDEAL [FP7-HEALTH-2010-two-stage-259679], Research and Education into Ageing-0153, European Regional Development Fund, Deelen J, Beekman M, Uh HW, Broer L, Ayers KL, Tan Q, Kamatani Y, Bennet AM, Tamm R, Trompet S, Guðbjartsson DF, Flachsbart F, Rose G, Viktorin A, Fischer K, Nygaard M, Cordell HJ, Crocco P, van den Akker EB, Böhringer S, Helmer Q, Nelson CP, Saunders GI, Alver M, Andersen-Ranberg K, Breen ME, van der Breggen R, Caliebe A, Capri M, Cevenini E, Collerton JC, Dato S, Davies K, Ford I, Gampe J, Garagnani P, de Geus EJ, Harrow J, van Heemst D, Heijmans BT, Heinsen FA, Hottenga JJ, Hofman A, Jeune B, Jonsson PV, Lathrop M, Lechner D, Martin-Ruiz C, McNerlan SE, Mihailov E, Montesanto A, Mooijaart SP, Murphy A, Nohr EA, Paternoster L, Postmus I, Rivadeneira F, Ross OA, Salvioli S, Sattar N, Schreiber S, Stefánsson H, Stott DJ, Tiemeier H, Uitterlinden AG, Westendorp RG, Willemsen G, Samani NJ, Galan P, Sørensen TI, Boomsma DI, Jukema JW, Rea IM, Passarino G, de Craen AJ, Christensen K, Nebel A, Stefánsson K, Metspalu A, Magnusson P, Blanché H, Christiansen L, Kirkwood TB, van Duijn CM, Franceschi C, Houwing-Duistermaat JJ, Slagboom PE., Leiden Univ, Dept Mol Epidemiol, NL-2300 RC Leiden, Netherlands [ 2 ] Leiden Univ, Netherlands Consortium Healthy Ageing, NL-2300 RC Leiden, Netherlands [ 3 ] Leiden Univ, Dept Med Stat & Bioinformat, NL-2300 RC Leiden, Netherlands [ 4 ] Leiden Univ, Dept Cardiol, NL-2300 RC Leiden, Netherlands [ 5 ] Leiden Univ, Dept Gerontol & Geriatr, NL-2300 RC Leiden, Netherlands [ 6 ] Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands [ 7 ] Erasmus MC, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands [ 8 ] Newcastle Univ, Int Ctr Life, Inst Med Genet, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England [ 9 ] Univ So Denmark, Inst Publ Hlth, DK-5000 Odense C, Denmark [ 10 ] Univ So Denmark, Inst Clin Res, Dept Gynecol & Obstet, DK-5000 Odense C, Denmark [ 11 ] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense C, Denmark [ 12 ] Odense Univ Hosp, Clin Biochem & Pharmacol, DK-5000 Odense C, Denmark [ 13 ] Fdn Jean Dausset CEPH, F-75010 Paris, France [ 14 ] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden [ 15 ] Univ Tartu, Estonian Genome Ctr, Tartu 51010, Estonia [ 16 ] Univ Tartu, Inst Mol & Cell Biol, EE-51010 Tartu, Estonia [ 17 ] deCODE Genet, Populat Gen, IS-101 Reykjavik, Iceland [ 18 ] Univ Kiel, Inst Clin Mol Biol, D-24105 Kiel, Germany [ 19 ] Univ Kiel, Inst Med Informat & Stat, D-24105 Kiel, Germany [ 20 ] Univ Calabria, Dept Biol Ecol & Earth Sci, I-87036 Arcavacata Di Rende, Italy [ 21 ] Delft Univ Technol, Delft Bioinformat Lab, NL-2600 GA Delft, Netherlands [ 22 ] Univ Leicester, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England [ 23 ] Glenfield Hosp, Cardiovasc Biomed Res Unit, Natl Inst Hlth Res, Leicester LE3 9QP, Leics, England [ 24 ] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SA, England [ 25 ] Queens Univ Belfast, Sch Med Dent & Biomed Sci, Belfast BT9 7BL, Antrim, North Ireland [ 26 ] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA [ 27 ] Univ Bologna, Dept Expt Diagnost & Specialty Med, I-40126 Bologna, Italy [ 28 ] Univ Bologna, Interdepartmental Ctr L Galvani, I-40126 Bologna, Italy [ 29 ] Newcastle Univ, Inst Ageing & Hlth, Newcastle Upon Tyne NE4 5PL, Tyne & Wear, England [ 30 ] Univ Glasgow, Robertson Ctr Biostat, Glasgow G12 8QQ, Lanark, Scotland [ 31 ] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow G12 8QQ, Lanark, Scotland [ 32 ] Max Planck Inst Demograf Forsch, Lab Stat Demog, D-18057 Rostock, Germany [ 33 ] Vrije Univ Amsterdam, Dept Biol Psychol, NL-1081 BT Amsterdam, Netherlands [ 34 ] Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, NL-1081 BT Amsterdam, Netherlands [ 35 ] Landspitali Univ Hosp, IS-101 Reykjavik, Iceland [ 36 ] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland [ 37 ] CEA, Inst Genom, F-91057 Evry, France [ 38 ] McGill Univ, Montreal, PQ H3G 1A4, Canada [ 39 ] Genome Quebec Innovat Ctr, Montreal, PQ H3G 1A4, Canada [ 40 ] Belfast Hlth & Social Care Trust, Cytogenet Lab, Belfast BT8 8BH, Antrim, North Ireland [ 41 ] Estonian Bioctr, EE-51010 Tartu, Estonia [ 42 ] Aarhus Univ, Dept Publ Hlth, Epidemiol Sect, DK-8000 Aarhus C, Denmark [ 43 ] Univ Bristol, Sch Social & Community Med, MRC Ctr Causal Anal Translat Epidemiol, Bristol BS8 2BN, Avon, England [ 44 ] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA [ 45 ] Univ Glasgow, Fac Med, BHF Glasgow Cardiovasc Res Ctr, Glasgow G12 8TA, Lanark, Scotland [ 46 ] Univ Kiel, PopGen Biobank, D-24105 Kiel, Germany [ 47 ] Univ Hosp Schleswig Holstein, D-24105 Kiel, Germany [ 48 ] Sophia Childrens Univ Hosp, Erasmus Med Ctr, Dept Child & Adolescent Psychiat, NL-3000 CA Rotterdam, Netherlands [ 49 ] Univ Paris 04, UREN, U557, INSERM, F-93017 Bobigny, France [ 50 ] U1125 Inra, F-93017 Bobigny, France [ 51 ] Cnam, F-93017 Bobigny, France [ 52 ] Univ Paris 13, CRNH IdF, F-93017 Bobigny, France [ 53 ] Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr, DK-2200 Copenhagen N, Denmark [ 54 ] Inst Prevent Med, DK-2000 Copenhagen, Denmark [ 55 ] Frederiksberg Univ Hosp, DK-2000 Copenhagen, Denmark [ 56 ] Interuniv Cardiol Inst Netherlands, NL-3501 DG Utrecht, Netherlands [ 57 ] Bellaria Hosp, IRCCS Inst Neurol Sci, I-40139 Bologna, Italy [ 58 ] CNR, ISOF, I-40129 Bologna, Italy, Epidemiology, Surgery, Internal Medicine, Child and Adolescent Psychiatry / Psychology, ProdInra, Migration, Vrije Universiteit Amsterdam [Amsterdam] (VU), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), VU University Amsterdam, Biological Psychology, and EMGO+ - Lifestyle, Overweight and Diabetes

Subjects
Male, Netherlands Twin Register (NTR), Disease/genetics, Lífslíkur, Longevity/genetics, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Genetic Linkage, Genome-wide association study, 0302 clinical medicine, Prospective Studies, Genetics (clinical), Genetics, Aged, 80 and over, 0303 health sciences, education.field_of_study, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Association Studies Articles, Age Factors, Chromosome Mapping, Genetic Loci/physiology, General Medicine, 3. Good health, Europe, Phenotype, Cardiovascular Diseases, Hypertension, Chromosomes, Human, Pair 5, Female, Human Longevity, genetics, meta-analysis, Aging/genetics, Cardiology and Cardiovascular Medicine, HUMAN AGING, Longevity, European Continental Ancestry Group, Population, HUMAN GENETICS, Single-nucleotide polymorphism, Locus (genetics), Biology, FAMILIAL LONGEVITY, White People, 03 medical and health sciences, Gene mapping, SDG 3 - Good Health and Well-being, Cardiovascular Diseases/genetics, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, Allele, education, Molecular Biology, Aged, 030304 developmental biology, Genetic association, Öldrun, Genome, Human, Arfgengi, Minor allele frequency, Ageing, Genetic Loci, Chromosomes, Human, Pair 19, Hypertension/genetics, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Genome-Wide Association Study
Abstract

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. The genetic contribution to the variation in human lifespan is ∼ 25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥ 85 years) and 16 121 younger controls (

Published
2014
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30. The geographic diversity of nontuberculous mycobacteria isolated from pulmonary samples: A NTM-NET collaborative study

Author

Eefje Jong, Monika Polanova, Kevin L. Winthrop, Tuula Vasankari, Tomasz Jagielski, Diego Domingo, Elia Palenque, Rosine Bauriaud, Miguel Villar, Mateja Janković, Joseph Keane, Rita Macedo, Dick van Soolingen, Renata Walkiewicz, Harald Hoffmann, Jakko van Ingen, Claire Andrejak, Raquel Cias, Frances Jamieson, Rachel Thomson, Sylvia Cardoso Leão, Elvira Richter, Martin J. Boeree, Kristian Ängeby, Charles L. Daley, Nalin Rastogi, Wo Jung Koh, Maryse Fauville-Dufaux, Po-Ren Hsueh, Dimitrios Papaventsis, Natalie Beylis, Rosa Daza, Noel Gibbons, Maria Jesus Ruiz-Serrano, Enrico Tortoli, Tamas Mlinkó, Berit Lange, Rosa Gonzalez, Jaime Esteban, Francis Drobniewski, Nora Szabó, Mar Paez-Peña, Alexander Indra, Heather Milburn, Kozo Morimoto, P. N. Richard Dekhuijzen, Teresa Fernandez, Anabela Santos Silva, Violet N. Chihota, Erica Chimara, Turid Mannsåker, Wouter Hoefsloot, Nora Morcillo, Gavin J. Churchyard, Jeannette Maugein, Dirk Wagner, Sarah E. Totten, Hülya Şimşek, Greg Tyrrell, Theodore K. Marras, Claudio Piersimoni, Enrique Gómez-Mampaso, Juana Cacho, Dorte Bek Folkvardsen, Pascale Bémer, M. Pedro Da Silva, Dept of Medical Microbiology, van Ingen (Jakko), Radboud University Medical Center [Nijmegen]-Radboud University Medical Center [Nijmegen], Departement of Clinical Microbiology, Karolinska Institutet [Stockholm], Laboratoire Central de Microbiologie, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Service de Bactériologie-Hygiène, Department of Microbiology, CHU Hôtel-Dieu, Lab. Fisica Aplicada, Department of Clinical Microbiology, Centre national de Référence et Laboratoire Tuberculose et Mycobactéries = National Reference Centre of Tuberculosis and Mycobacteria [Brussels] (CNR), Institut Scientifique de Santé Publique [Belgique] - Scientific Institute of Public Health [Belgium] (WIV-ISP), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), LPI, Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER), Department of Applied Microbiology [Warsaw], Institute of Microbiology [Warsaw], Faculty of Biology [Warsaw], University of Warsaw (UW)-University of Warsaw (UW)-Faculty of Biology [Warsaw], University of Warsaw (UW)-University of Warsaw (UW), Institut Pasteur de la Guadeloupe, Réseau International des Instituts Pasteur (RIIP), Centro Regionale di Riferimento per i Micobatteri, Ospedale Careggi-Laboratorio di Microbiologia e Virologia, General Directorate of Health, Radboud Univ Nijmegen, Amiens Teaching Hosp, Karolinska Inst, Hop Purpan, CHU Nantes, Natl Hlth Lab Serv, Univ Hosp Getafe, Aurum Inst Hlth Res, Adolfo Lutz Inst, Hosp Clin San Carlos, Hosp Univ Puerta de Hierro, Natl Jewish Hlth, Hosp Univ Princesa, UK Hlth Protect Agcy, IIS Fdn Jimenez Diaz, Sci Inst Publ Hlth, Statens Serum Inst, St James Hosp, Univ Dublin Trinity Coll, Hosp Ramon & Cajal, Hosp Univ Principe Asturias, Asklepios Facbkliniken, Natl Taiwan Univ Hosp, Austrian Agcy Hlth & Food Safety, Univ Warsaw, Ontario Minist Hlth & Long Term Care, Univ Zagreb Med Sch, Univ Witwatersrand, St Jamess Hosp Dublin, Sungkyunkwan Univ Sch Med, Univ Hosp Freiburg, Universidade Federal de São Paulo (UNIFESP), Adm Reg Saude Lisboa & Vale Tejo, Norwegian Inst Publ Hlth, Univ Toronto, Univ Victor Segalen Bordeaux, Guys & St Thomas NHS Fdn Trust, Koranyi Natl Inst TB & Pulmonol, Hosp Dr Antonio Cetrangolo, Fukujuji Hosp, Sotiria Chest Dis Hosp, Hosp 12 Octubre, Hosp Severo Ochoa, United Hosp, Natl Inst TB Resp Dis & Chest Surg, Inst Pasteur Guadeloupe, Natl Reference Ctr Mycobacteria, Hosp Gregorio Maranon, Gen Directorate Hlth Lisbon, Lung Dis Ctr Venda Nova, Refik Saydam Natl Publ Hlth Agcy, Natl Inst Publ Hlth & Environm, Koranyi Natl Inst TB & Resp Med, Greenslopes Private Hosp, Hosp Val dHebron, Ist Sci San Raffaele, Univ Calgary, Natl Inst Hlth & Welf, Med Univ Warsaw, Oregon Hlth & Sci Univ, Univ Freiburg, Laboratoire de Physiologie des Invertébrés (LPI), Physiologie Fonctionnelle des Organismes Marins (PFOM), and Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)

Subjects
Lung Diseases, Veterinary medicine, Mycobacterium bohemicum, Mycobacterium lentiflavum, Species distribution, Global Health, Poverty-related infectious diseases Infection and autoimmunity [N4i 3], Species identification, Lung, Nontuberculous mycobacteria, Mycobacterium interjectum, 0303 health sciences, Geography, biology, Atypical mycobacteria, Mycobacterium abscessus, Ecology, Mycobacterium fortuitum, Relative distribution, nontuberculous mycobacteria, geographical diversity, Mycobacterium scrofulaceum, Mycobacterium malmoense, 3. Good health, Mycobacterium gordonae, Pathogenesis and modulation of inflammation [N4i 1], Mycobacterium kansasii, NTM, Worldwide distribution, Poverty-related infectious diseases Aetiology, screening and detection [N4i 3], Pulmonary and Respiratory Medicine, Mycobacterium xenopi, Tuberculosis, Mycobacterium smegmatis, Mycobacterium simiae, Mycobacterium Infections, Nontuberculous, Mycobacterium, 03 medical and health sciences, Species Specificity, medicine, Humans, Mycobacterium avium complex, 030304 developmental biology, 030306 microbiology, Poverty-related infectious diseases [N4i 3], Respiratory infections, Geographic diversity, medicine.disease, biology.organism_classification, bacterial infections and mycoses, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Mycobacterium intracellulare, Pulmonary infections, Mycobacterium avium
Abstract

German Federal Ministry of Education and Research A significant knowledge gap exists concerning the geographical distribution of nontuberculous mycobacteria (NTM) isolation worldwide.To provide a snapshot of NTM species distribution, global partners in the NTM-Network European Trials Group (NET) framework (www.ntm-net.org), a branch of the Tuberculosis Network European Trials Group (TB-NET), provided identification results of the total number of patients in 2008 in whom NTM were isolated from pulmonary samples. From these data, we visualised the relative distribution of the different NTM found per continent and per country.We received species identification data for 20182 patients, from 62 laboratories in 30 countries across six continents. 91 different NTM species were isolated. Mycobacterium avium complex (MAC) bacteria predominated in most countries, followed by M. gordonae and M. xenopi. Important differences in geographical distribution of MAC species as well as M. xenopi, M. kansasii and rapid-growing mycobacteria were observed.This snapshot demonstrates that the species distribution among NTM isolates from pulmonary specimens in the year 2008 differed by continent and differed by country within these continents. These differences in species distribution may partly determine the frequency and manifestations of pulmonary NTM disease in each geographical location. Radboud Univ Nijmegen, Med Ctr, Dept Pulm Dis, NL-6500 HB Nijmegen, Netherlands Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, NL-6500 HB Nijmegen, Netherlands Amiens Teaching Hosp, Dept Resp Dis, Amiens, France Karolinska Inst, Dept Clin Microbiol, Stockholm, Sweden Hop Purpan, Lab Cent Microbiol, Toulouse, France CHU Nantes, Inst Biol, Serv Bacteriol Hyg, F-44035 Nantes 01, France Natl Hlth Lab Serv, Braamfontein, South Africa Univ Hosp Getafe, Dept Microbiol, Getafe, Spain Aurum Inst Hlth Res, Johannesburg, South Africa Adolfo Lutz Inst, Secao Bacteriol, Setor Micobacterias, São Paulo, Brazil Hosp Clin San Carlos, Dept Clin Microbiol, Madrid, Spain Hosp Univ Puerta de Hierro, Dept Microbiol, Madrid, Spain Natl Jewish Hlth, Div Mycobacterial & Resp Infect, Denver, CO USA Hosp Univ Princesa, Dept Microbiol, Madrid, Spain UK Hlth Protect Agcy, Natl Mycobacterium Reference Lab, London, England IIS Fdn Jimenez Diaz, Dept Clin Microbiology, Madrid, Spain Sci Inst Publ Hlth, Natl Reference Ctr TB & Mycobacteria, Brussels, Belgium Statens Serum Inst, Int Reference Lab Mycobacteriol, DK-2300 Copenhagen, Denmark St James Hosp, Dublin 8, Ireland Univ Dublin Trinity Coll, Dublin 2, Ireland Hosp Ramon & Cajal, E-28034 Madrid, Spain Hosp Univ Principe Asturias, Madrid, Spain Asklepios Facbkliniken, Supranat Reference Lab, Inst Microbiol & Lab Med, Gauting, Germany Natl Taiwan Univ Hosp, Dept Lab Med, Taipei, Taiwan Natl Taiwan Univ Hosp, Dept Internal Med, Taipei 100, Taiwan Austrian Agcy Hlth & Food Safety, Vienna, Austria Univ Warsaw, Fac Biol, Inst Microbiol, Dept Appl Microbiol, Warsaw, Poland Ontario Minist Hlth & Long Term Care, Publ Hlth Labs Branch, Toronto, ON, Canada Univ Zagreb Med Sch, Univ Hosp Ctr, Dept Resp Dis, Zagreb, Croatia Univ Witwatersrand, Clin HIV Res Unit, Johannesburg, South Africa St Jamess Hosp Dublin, Dublin, Ireland Sungkyunkwan Univ Sch Med, Samsung Med Ctr, Dept Med, Div Pulm & Crit Care Med, Seoul, South Korea Univ Hosp Freiburg, Ctr Infect Dis & Travel Med, Freiburg, Germany Universidade Federal de São Paulo, Escola Paulista Med, Dept Microbiol Imunol & Parasitol, Disciplina Microbiol, São Paulo, Brazil Adm Reg Saude Lisboa & Vale Tejo, Dept Publ Hlth, Publ Hlth Lab Mycobacteriol TB, Lisbon, Portugal Norwegian Inst Publ Hlth, Div Infect Dis Control, Oslo, Norway Univ Toronto, Univ Hlth Network, Joint Div Respirol, Toronto, ON, Canada Univ Toronto, Mt Sinai Hosp, Dept Med, Toronto, ON M5G 1X5, Canada Univ Victor Segalen Bordeaux, Lab Bacteriol, Bordeaux, France Guys & St Thomas NHS Fdn Trust, Dept Resp Med, London, England Koranyi Natl Inst TB & Pulmonol, Budapest, Hungary Hosp Dr Antonio Cetrangolo, Programa Control TB Prov Buenos Aires, Lab Referencia, Buenos Aires, Brazil Fukujuji Hosp, Japan AntiTB Assoc, Tokyo, Japan Sotiria Chest Dis Hosp, Natl Mycobacteria Reference Lab, Athens, Greece Hosp 12 Octubre, Dept Microbiol, E-28041 Madrid, Spain Hosp Severo Ochoa, Madrid, Spain United Hosp, Reg Reference Mycobacteria Lab, Ancona, Italy Natl Inst TB Resp Dis & Chest Surg, Vysne Hagy, Slovakia Inst Pasteur Guadeloupe, Unite TB & Mycobacteries, WHO Supranat TB Reference Lab, Abymes, Guadeloupe Natl Reference Ctr Mycobacteria, Borstel, Germany Hosp Gregorio Maranon, Serv Microbiol Clin & Enfermedades Infecciosas, Madrid, Spain Gen Directorate Hlth Lisbon, Amadora, Portugal Lung Dis Ctr Venda Nova, Amadora, Portugal Univ Witwatersrand, Johannesburg, South Africa Refik Saydam Natl Publ Hlth Agcy, Natl TB Reference Lab, Ankara, Turkey Natl Inst Publ Hlth & Environm, NL-3720 BA Bilthoven, Netherlands Koranyi Natl Inst TB & Resp Med, Budapest, Hungary Greenslopes Private Hosp, Gallipoli Med Res Ctr, Brisbane, Qld, Australia Hosp Val dHebron, Barcelona, Spain Ist Sci San Raffaele, Emerging Bacterial Pathogens Unit, I-20132 Milan, Italy Natl Jewish Hlth, Adv Diagnost Labs, Dept Mycobacteriol, Denver, CO USA Univ Calgary, Prov Lab Publ Hlth, Calgary, AB, Canada Natl Inst Hlth & Welf, Epidemiol Surveillance & Response Unit, Dept Infect Dis Surveillance & Control, Helsinki, Finland Med Univ Warsaw, Dept Internal Med Pneumol & Allergol, Warsaw, Poland Oregon Hlth & Sci Univ, Div Infect Dis Publ Hlth & Prevent Med, Portland, OR 97201 USA Univ Freiburg, Dept Internal Med Infect Dis 2, D-79106 Freiburg, Germany Universidade Federal de São Paulo, Escola Paulista Med, Dept Microbiol Imunol & Parasitol, Disciplina Microbiol, São Paulo, Brazil German Federal Ministry of Education and Research: BMBF 01 EO 0803 Web of Science

Published
2013
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31. Genome-wide association analysis identifies 13 new risk loci for schizophrenia

Author

Ripke, S, O'Dushlaine, C, Chambert, K, Moran, Jl, Kähler, Ak, Akterin, S, Bergen, Se, Collins, Al, Crowley, Jj, Fromer, M, Kim, Y, Lee, Sh, Magnusson, Pk, Sanchez, N, Stahl, Ea, Williams, S, Wray, Nr, Xia, K, Bettella, F, Borglum, Ad, Bulik Sullivan, Bk, Cormican, P, Craddock, N, Leeuw, De, C, Durmishi, N, Gill, M, Golimbet, V, Hamshere, Ml, Holmans, P, Hougaard, Dm, Kendler, Ks, Lin, K, Morris, Dw, Mors, O, Mortensen, Pb, Neale, Bm, O'Neill, Fa, Owen, Mj, Milovancevic, Mp, Posthuma, D, Powell, J, Richards, Al, Riley, Bp, Ruderfer, D, Rujescu, D, Sigurdsson, E, Silagadze, T, Smit, Ab, Stefansson, H, Steinberg, S, Suvisaari, J, Tosato, Sarah, Verhage, M, Walters, Jt, Multicenter Genetic Studies of Schizophrenia Consortium, Levinson, Df, Gejman, Pv, Laurent, C, Mowry, Bj, O'Donovan, Mc, Pulver, Ae, Schwab, Sg, Wildenauer, Db, Dudbridge, F, Shi, J, Albus, M, Alexander, M, Campion, D, Cohen, D, Dikeos, D, Duan, J, Eichhammer, P, Godard, S, Hansen, M, Lerer, Fb, Liang, Ky, Maier, W, Mallet, J, Nertney, Da, Nestadt, G, Norton, N, Papadimitriou, Gn, Ribble, R, Sanders, Ar, Silverman, Jm, Walsh, D, Williams, Nm, Wormley, B, Psychosis Endophenotypes International Consortium, Arranz, Mj, Bakker, S, Bender, S, Bramon, E, Collier, D, Crespo Facorro, B, Hall, J, Iyegbe, C, Jablensky, A, Kahn, Rs, Kalaydjieva, L, Lawrie, S, Lewis, Cm, Linszen, Dh, Mata, I, Mcintosh, A, Murray, Rm, Ophoff, Ra, Van, Os, J, Walshe, M, Weisbrod, M, Wiersma, D, Wellcome Trust Case Control Consortium 2, Donnelly, P, Barroso, I, Blackwell, Jm, Brown, Ma, Casas, Jp, Corvin, Ap, Deloukas, P, Duncanson, A, Jankowski, J, Markus, Hs, Mathew, Cg, Palmer, Cn, Plomin, R, Rautanen, A, Sawcer, Sj, Trembath, Rc, Viswanathan, Ac, Wood, Nw, Spencer, Cc, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, Rd, Strange, A, Su, Z, Vukcevic, D, Langford, C, Hunt, Se, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, Sj, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, Mccann, Ot, Liddle, J, Potter, Sc, Ravindrarajah, R, Ricketts, M, Tashakkori Ghanbaria, A, Waller, Mj, Weston, P, Widaa, S, Whittaker, P, Mccarthy, Mi, Stefansson, K, Scolnick, E, Purcell, S, Mccarroll, Sa, Sklar, P, Hultman, Cm, Sullivan, P. F., Functional Genomics, Molecular and Cellular Neurobiology, AIMMS, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Adult Psychiatry, Ripke, Stephan, O'Dushlaine, Colm, Chambert, Kimberly, Moran, Jennifer L, Lee, Sang Hong, Sullivan, Patrick F, Multicenter Genetic Studies of Schizophrenia Consortium, Psychosis Endophenotypes International Consortium, Wellcome Trust Case Control Consortium 2, Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA Univ N Carolina, Dept Genet, Chapel Hill, NC 27515 USA Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden Oslo Univ Hosp, Div Mental Hlth & Addict, Oslo, Norway Icahn Sch Med Mt Sinai, Dept Psychiat, Div Psychiat Genom, New York, NY USA Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA deCODE Genet, Reykjavik, Iceland Aarhus Univ Hosp, Risskov, Denmark Aarhus Univ, Ctr Integrat Sequencing iSEQ, Aarhus, Denmark Lundbeck Fdn Initiat Integrat Psychiat Res iPSYCH, Aarhus, Denmark Lundbeck Fdn Initiat Integrat Psychiat Res iPSYCH, Copenhagen, Denmark Univ Dublin Trinity Coll, Dept Psychiat, Dublin 2, Ireland Cardiff Univ, Sch Med, Ctr Psychiat Genet & Genom, MRC, Cardiff CF10 3AX, S Glam, Wales Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Funct Genom, Amsterdam, Netherlands Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands Radboud Univ Nijmegen, Inst Comp & Informat Sci, NL-6525 ED Nijmegen, Netherlands Univ Clin Psychiat, Dept Child & Adolescent Psychiat, Skopje, Macedonia Univ Dublin Trinity Coll, Neuropsychiat Genet Res Grp, Dublin 2, Ireland Russian Acad Med Sci, Mental Hlth Res Ctr, Moscow 109801, Russia Statens Serum Inst, DK-2300 Copenhagen, Denmark Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA USA Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA USA Kings Coll London, Inst Psychiat, London, England Aarhus Univ Hosp, Ctr Psychiat Res, Risskov, Denmark Aarhus Univ, Natl Ctr Register Based Res, Aarhus, DenmarkQueens Univ Belfast, Ctr Publ Hlth, Belfast, Antrim, North Ireland Univ Belgrade, Fac Med, Belgrade, Serbia Erasmus Univ, Med Ctr, Dept Child & Adolescent Psychiat, Rotterdam, Netherlands Kings Coll London, Dept Neurosci, London, England Virginia Commonwealth Univ, Dept Human & Mol Genet, Richmond, VA USA Univ Halle, Dept Psychiat, Halle, Germany Univ Munich, Dept Psychiat, D-80539 Munich, Germany Univ Iceland, Dept Psychiat, Reykjavik, Iceland Landspitali University Hospital Reykjavik, Iceland Tbilisi State Univ, Dept Psychiat, GE-380086 Tbilisi, Rep of Georgia Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Amsterdam, Netherlands Vrije Univ Amsterdam, Dept Mol & Cellular Neurosci, Amsterdam, Netherlands Natl Inst Hlth & Welf, Mental Hlth & Subst Abuse Serv, Helsinki, Finland Univ Verona, Sect Psychiat, I-37100 Verona, Italy UCL, Inst Cognit Neurosci, London, England UCL, Mental Hlth Sci Unit, London, England Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA Harvard Univ, Sch Med, Dept Genet, Boston, MA USA, Child and Adolescent Psychiatry / Psychology, Psychiatrie & Neuropsychologie, RS: MHeNs School for Mental Health and Neuroscience, Human genetics, NCA - Brain mechanisms in health and disease, and NCA - Neurobiology of mental health

Subjects
Male, Candidate gene, SNP, Single-nucleotide polymorphism, Genome-wide association study, Disease, Biology, heritability, neuronal calcium signaling, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Genetics, medicine, Humans, GWAS, Genetic Predisposition to Disease, Bipolar disorder, 030304 developmental biology, Genetic association, Sweden, Genetics & Heredity, 0303 health sciences, medicine.disease, 3. Good health, genome sequencing, schizophrenia, Schizophrenia, Meta-analysis, Case-Control Studies, genetic variation, Female, genome-wide scan, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field. Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder. NIMH R01 MH077139 R01 MH095034 Stanley Center for Psychiatric Research Sylvan Herman Foundation Friedman Brain Institute at the Mount Sinai School of Medicine Karolinska Institutet, Karolinska University Hospital Swedish Research Council Swedish County Council Soderstrom Konigska Foundation Netherlands Scientific Organization NWO 645-000-003 info:eu-repo/grantAgreement/EC/FP7/223423 Danish Strategic Research Council H. Lundbeck A/S Faculty of Health Sciences at Aarhus University Lundbeck Foundation Stanley Research Foundation Wellcome Trust 085475/B/08/Z 085475/Z/08/Z

Published
2013
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32. 3D VMAT Verification Based on Monte Carlo Log File Simulation with Experimental Feedback from Film Dosimetry

Author

Antonio Leal, S. Velazquez, J.A. Baeza, A.R. Barbeiro, Juan Carlos Rodríguez Mateos, E. Jimenez-Ortega, Ana Ureba, M. Perucha, R. Linares, Ministerio de Ciencia y Tecnología (España), European Commission, Junta de Andalucía, [Barbeiro, A. R.] Univ Seville, Dept Fisiol Med & Biofis, Seville, Spain, [Ureba, A.] Univ Seville, Dept Fisiol Med & Biofis, Seville, Spain, [Baeza, J. A.] Univ Seville, Dept Fisiol Med & Biofis, Seville, Spain, [Jimenez-Ortega, E.] Univ Seville, Dept Fisiol Med & Biofis, Seville, Spain, [Mateos, J. C.] Univ Seville, Dept Fisiol Med & Biofis, Seville, Spain, [Leal, A.] Univ Seville, Dept Fisiol Med & Biofis, Seville, Spain, [Linares, R.] Hosp Infanta Luisa, Serv Radiofis, Seville, Spain, [Perucha, M.] Hosp Infanta Luisa, Serv Radiofis, Seville, Spain, [Velazquez, S.] Hosp Virgen del Rocio, Serv Radiofis, Seville, Spain, [Mateos, J. C.] Hosp Virgen del Rocio, Serv Radiofis, Seville, Spain, [Barbeiro, A. R.] Inst Biomed Sevilla, IBIS, Seville, Spain, [Ureba, A.] Inst Biomed Sevilla, IBIS, Seville, Spain, [Perucha, M.] Inst Biomed Sevilla, IBIS, Seville, Spain, [Jimenez-Ortega, E.] Inst Biomed Sevilla, IBIS, Seville, Spain, [Velazquez, S.] Inst Biomed Sevilla, IBIS, Seville, Spain, [Leal, A.] Inst Biomed Sevilla, IBIS, Seville, Spain, [Ureba, A.] Stockholm Univ, Karolinska Inst, Med Radiat Phys, Stockholm, Sweden, [Baeza, J. A.] Maastricht Univ, Med Ctr, Dept Radiat Oncol, Maastricht, Netherlands, Spanish Ministry of Science and Technology, and European Regional Development Fund

Subjects
Male, System, Statistical methods, Phantom, Computer science, medicine.medical_treatment, Monte Carlo method, Cancer Treatment, lcsh:Medicine, 030218 nuclear medicine & medical imaging, Geographical Locations, 0302 clinical medicine, Volumetric modulated arc, Medicine and Health Sciences, lcsh:Science, Rapidarc, Radiation treatment planning, Multidisciplinary, Phantoms, Imaging, Simulation and Modeling, Physics, Applied Mathematics, Passing rates, Quality-assurance method, Cancer treatment, Physical sciences, Europe, Oncology, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Ionization chamber, Anatomy, Monte Carlo Method, Delivery, Algorithm, Algorithms, Research Article, Clinical Oncology, medicine.medical_specialty, Film Dosimetry, Discretization, Biophysics, Radiation Therapy, Statistics (mathematics), Research and Analysis Methods, Imaging phantom, Feedback, 03 medical and health sciences, Exocrine Glands, Robustness (computer science), Dosimetry, Histogram, medicine, Humans, Computer Simulation, Medical physics, Monaco, lcsh:R, Biology and Life Sciences, Prostatic Neoplasms, Models, Theoretical, Volumetric modulated arc therapy, Radiation therapy, People and Places, Mathematical and statistical techniques, Prostate Gland, lcsh:Q, Radiotherapy, Intensity-Modulated, Therapy, Clinical Medicine, Imrt, Qa, Mathematics
Abstract

A model based on a specific phantom, called QuAArC, has been designed for the evaluation of planning and verification systems of complex radiotherapy treatments, such as volumetric modulated arc therapy (VMAT). This model uses the high accuracy provided by the Monte Carlo (MC) simulation of log files and allows the experimental feedback from the high spatial resolution of films hosted in QuAArC. This cylindrical phantom was specifically designed to host films rolled at different radial distances able to take into account the entrance fluence and the 3D dose distribution. Ionization chamber measurements are also included in the feedback process for absolute dose considerations. In this way, automated MC simulation of treatment log files is implemented to calculate the actual delivery geometries, while the monitor units are experimentally adjusted to reconstruct the dose-volume histogram (DVH) on the patient CT. Prostate and head and neck clinical cases, previously planned with Monaco and Pinnacle treatment planning systems and verified with two different commercial systems (Delta4 and COMPASS), were selected in order to test operational feasibility of the proposed model. The proper operation of the feedback procedure was proved through the achieved high agreement between reconstructed dose distributions and the film measurements (global gamma passing rates > 90% for the 2%/2 mm criteria). The necessary discretization level of the log file for dose calculation and the potential mismatching between calculated control points and detection grid in the verification process were discussed. Besides the effect of dose calculation accuracy of the analytic algorithm implemented in treatment planning systems for a dynamic technique, it was discussed the importance of the detection density level and its location in VMAT specific phantom to obtain a more reliable DVH in the patient CT. The proposed model also showed enough robustness and efficiency to be considered as a pre-treatment VMAT verification system., This work was supported by the Spanish Ministry of Science and Technology (SAF2011-27116; IPT-2011-1480-900000) and the European Regional Development Fund.

Published
2016
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33. Allergic Rhinitis and its Impact on Asthma (ARIA): Achievements in 10 years and future needs

Author

Bousquet, Jean, Schunemann, H. J., Samolinski, B., Demoly, Pascal, Baena-Cagnani, C. E., Bachert, C., Bonini, S., Boulet, L. P., Brozek, J. L., Canonica, G. W., Casale, T. B., Cruz, A. A., Fokkens, W. J., Fonseca, J. A., Wick, R. G. van, Grouse, L., Haahtela, T., Khaltaev, N., Kuna, P., Lockey, R. F., Carlsen, K. C. Lodrup, Mullol, J., Naclerio, R. N., O'Hehir, R. E., Ohta, K., Palkonen, S., Papadopoulos, N. G., Passalacqua, G., Pawankar, R., Price, D., Ryan, D., Simons, F. E. R., Togias, A., Williams, D. M., Yorgancioglu, A., Yusuf, O. M., Aberer, W., Adachi, M., Agache, I., Aït-Khaled, N., Akdis, C. A., Andrianarisoa, A., Annesi-Maesano, I., Ansotegui, I. J., Baiardini, I., Bateman, E. D., Bedbrook, Anna, Beghé, B., Beji, M., Bel, E. H., Kheder, A. Ben, Bennoor, K. S., Bergmann, K. C., Berrissoul, F., Bieber, T., Bindslev-Jensen, C., Blaiss, M. S., Boner, A. L., Bouchard, J., Braido, F., Brightling, C. E., Bush, A., Caballero-Fonseca, F., Calderon, M. A., Calvo, M. A., Camargos, P. A. M., Caraballo, L. R., Carlsen, K. H., Carr, W., A.M, Cepeda Sarabia, Cesario, A., Chavannes, Niels H., Chen, Y. Z., Chiriac, A. M., Pérez, T. Chivato, Chkhartishvili, E., Ciprandi, G., Costa, David J., Cox, L., Custovic, Adnan, Dahl, R., Darsow, U., Blay, F. De, Deleanu, D., Denburg, J. A., Devillier, P., Didi, T., Dokic, D., Dolen, W. K., Douagui, H. B., Dubakiene, R., Durham, S. R., Dykewicz, M. S., El-Gamal, Y., El-Meziane, A., Emuzyte, R., Fiocchi, A., Fletcher, M., Fukuda, T., Gamkrelidze, A., Gereda, J. E., Diaz, S. González, Gotua, M., Guzmán, M. A., Hellings, P. W., Hellquist-Dahl, B., Horak, F., Hourihane, J. O. B., Howarth, P. H., Humbert, M., Ivancevich, J. C., Jackson, Rod T., Just, J., Kalayci, O., Kaliner, M. A., Kalyoncu, A. F., Keil, T., Keith, P. K., Khayat, G., Kim, Y. Y., N'Goran, B. Koffi, Koppelman, G. H., Kowalski, M. L., Kull, I., Kvedariene, V., Larenas-Linnemann, D., Le, Tuyen D., Lemière, C., Li, J., Lieberman, P., Lipworth, B. J., Mahboub, B., Makela, M. J., Martin, F., Marshall, G. D., Martinez, F. D., Masjedi, M. R., Maurer, M., Mavale-Manuel, S., Mazon, A., Melén, E., Meltzer, E. O., Mendez, N. H., Merk, H., Mihaltan, F., Mohammad, Y., Almeida, M. Morais, Muraro, A., Nafti, S., Namazova-Baranova, L., Nekam, K., Neou, A., Niggemann, B., Nizankowska-Mogilnicka, E., Nyembue, T. D., Okamoto, Y., Okubo, K., Orru, M. P., Ouedraogo, S., Ozdemir, C., Panzner, P., Pali-Schöll, I., Park, H. S., Pigearias, B., Pohl, W., Popov, T. A., Postma, D. S., Potter, P., Rabe, K. F., Ratomaharo, J., Reitamo, S., Ring, J., Roberts, R., Rogala, B., Romano, A., Rodriguez, M. Roman, Rosado-Pinto, J., Rosenwasser, L., Rottem, M., Sanchez-Borges, M., Scadding, G. K., Schmid-Grendelmeier, P., Sheikh, A., Sisul, J. C., Sole, D., Sooronbaev, T., Spicak, V., Spranger, O., Stein, R. T., Stoloff, S. W., Sunyer, Jordi, Szczeklik, A., Todo-Bom, A., Toskala, E., Tremblay, Y., Valenta, R., Valero, A. L., Valeyre, D., Valiulis, A., Valovirta, E., Cauwenberge, P. Van, Vandenplas, O., Weel, C. Van, Vichyanond, P., Viegi, Giovanni, Wang, D. Y., Wickman, M., Wöhrl, S., Wright, J., Yawn, B. P., Yiallouros, Panayiotis K., Zar, H. J., Zernotti, M. E., Zhong, N., Zidarn, M., Zuberbier, T., Ang, C. S., Baigenzhin, A. K., Boakye, D. A., Briggs, A. H., Burney, P. G., Busse, W. W., Chuchalin, Alexander G., Haddad, H., Johnston, S. L., Kogevinas, M., Levy, L. M., Mohammadi, A., Oddie, S., Rezagui, D., Terreehorst, I., Warner, J. O., Bousquet, J, Schünemann, Hj, Samolinski, B, Demoly, P, Baena Cagnani, Ce, Bachert, C, Bonini, Sergio, AII - Amsterdam institute for Infection and Immunity, Ear, Nose and Throat, Pulmonology, Yiallouros, Panayiotis K. [0000-0002-8339-9285], Custovic, Adnan [0000-0001-5218-7071], Hop Arnaud Villeneuve, INSERM, McMaster Univ, Med Univ Warsaw, Univ Hosp Montpellier, Catholic Univ, Univ Genoa, Univ Ghent, CNR, Univ Naples 2, Univ Laval, Creighton Univ, Universidade Federal da Bahia (UFBA), CNPq, Univ Amsterdam, Univ Porto, Hosp S Joao & Inst, Hosp CUF Porto, Erasmus MC, Univ Washington, Helsinki Univ Hosp, GARD ARIA Coordinator, Med Univ Lodz, Univ S Florida, James A Haley Vet Hosp, Univ Oslo, CIBERES, Univ Chicago, Alfred Hosp, Monash Univ, Teikyo Univ, EFA European Federat Allergy & Airways Dis Patien, Univ Athens, Nippon Med Sch, Univ Aberdeen, Woodbrook Med Ctr, Univ Edinburgh, Univ Manitoba, NIAID, Univ N Carolina, Celal Bayar Univ, Allergy & Asthma Inst, Med Univ Graz, Showa Univ, Transylvania Univ, Int Union TB & Lung Dis Union, Univ Zurich, Minist Hlth, Univ Paris 06, Hosp Quiron Bizkaia, Univ Cape Town, WHO, Univ Modena & Reggio Emilia, Ctr Hosp Univ Rabta, Hop Mami, Bangladesh Lung Fdn, Natl Inst Dis Chest & Hosp, Charite, Univ Med Ctr, Odense Univ Hosp, Univ Tennessee, Univ Verona, Hop Malbaie, Univ Leicester, Royal Brompton Hosp, Univ London Imperial Coll Sci Technol & Med, Ctr Med Docente La Trinidad Caracas, Univ Austral Chile, Univ Fed Sao Joao del Rei, Univ Cartagena, So Calif Res, Metropolitan Univ Barranquilla, IRCCS San Raffaele Pisana, Univ Cattolica Sacro Cuore, Leiden Univ, Capital Inst Pediat, Ctr Asthma Res & Educ, Univ Hosp, Georgian Natl Univ, Univ Montpellier I, Nova SE Univ, Univ Manchester, Aarhus Univ Hosp, Tech Univ Munich, TUM, Univ Hosp Strasbourg, Univ Med & Pharm Iuliu Hatieganu, Univ Versailles St Quentin, Ctr Hosp Reg Annecy, Univ Ss Cyril & Methodius, Georgia Hlth Sci Univ, Ctr Hosp Univ Beni Messous, Vilnius Univ, Wake Forest Univ, Ain Shams Univ, Egyptian Soc Pediat Allergy & Immunol, Soc Marocaine Malad Resp, Ctr Resp Dis & Allergy, Univ Milan, Educ Hlth, Dokkyo Med Univ, Clin Ricardo Palma, Univ Nuevo Leon UANL, Ctr Allergy & Immunol, Clin Hosp Univ Chile, Univ Hosp Leuven, Cent Reg Denmark, Allergy Ctr Vienna W, Natl Univ Ireland Univ Coll Cork, Univ Southampton, Univ Paris 11, Salvador Univ, Univ St Andrews, Univ Paris, Hacettepe Univ, George Washington Univ, Inst Asthma & Allergy, Hacettepe Univ Hosp, Hotel Dieu France, Univ St Joseph, Natl Med Ctr, Seoul Natl Univ, Korea Asthma Allergy Fdn, Ctr Hosp Univ, Univ Groningen, Karolinska Inst, Vilnius Univ Hosp Santariskiu Klinikos, Hosp Med Sur, Univ Med & Pharm, Hop Sacre Coeur Montreal, Univ Montreal, Guangzhou Med Univ, Univ Dundee, Dubai Hlth Author, Univ Sharjah, Univ Mississippi, Univ Arizona, Shahid Beheshti Univ Med Sci, Universidade Estadual de Maringá (UEM), Eduardo Mondlane Univ, Childrens Hosp La Fe, Karolinska Univ Hosp, Univ Calif San Diego, IMSS, Univ Aachen, Inst Pneumol Marius Nasta, Tishreen Univ, CUF Descobertas Hosp, Univ Padua, Mustapha Hosp, Sci Ctr Childrens Hlth RAMS, Hosp Hospitaller Bros Buda, German Red Cross Hosp Westend, Jagiellonian Univ, Kinshasa Univ, Chiba Univ Hosp, Ctr Hosp Univ Pediat Charles de Gaulle, Marmara Univ, Mem Hlth Grp, Charles Univ Prague, MESSERLI Res Inst, Med Univ Vienna, Univ Vienna, Ajou Univ, NICE, Soc Pneumol Langue Francaise, Krankenhaus Hietzing, Alexanders Univ Hosp, Groote Schuur Hosp, Grosshansdorf Clin, Hop Prive Athis Mons, Univ Wisconsin, Med Univ Silesia, Complesso Integrato Columbus, IRCCS Oasi Maria SS, Son Pisa Primary Care Ctr, Hosp Luz, Univ Missouri, Childrens Mercy Hosp, Emek Med Ctr, Technion Israel Inst Technol, Ctr Med Docente La Trinidad, UCL, Univ Zurich Hosp, Universidade Federal de São Paulo (UNIFESP), Natl Ctr Cardiol & Internal Med, Ctr ACI Immunoflow, GAAPP, Ctr Res Environm Epidemiol CREAL, Pontificia Univ Catolica RGS, Univ Nevada, Hosp Mar, CIBER Epidemiol & Salud Publ CIBERESP, Univ Pompeu Fabra UPF, Coimbra Univ Hosp, Childrens Hosp Philadelphia, Finnish Inst Occupat Hlth, Hosp Clin Barcelona, IDIBAPS, Univ Paris 13, Avicenne Hosp, Lithuanian Natl Council Childs Hlth, Terveystalo Turku, Univ Turku, Catholic Univ Louvain, Radboud Univ Nijmegen, Siriraj Hosp, Clin Physiol IFC, Natl Univ Singapore, Floridsdorf Allergy Ctr FAZ, Bradford Teaching Hosp Fdn Trust, Olmsted Med Ctr, Univ Minnesota, Harvard Univ, Cyprus Univ Technol, Catholic Univ Cordoba, Univ Clin Resp & Allerg Dis, Faculteit Medische Wetenschappen/UMCG, Groningen Research Institute of Pharmacy, Groningen Research Institute for Asthma and COPD (GRIAC), Dermatology, Internal Medicine, Erasmus MC other, Göğüs Hastalıkları, UCL - (MGD) Service de pneumologie, and UCL - SSS/IREC/PNEU - Pôle de Pneumologie, ORL et Dermatologie

Subjects
Allergy, WORLD-HEALTH-ORGANIZATION, GUIDELINES, Medical and Health Sciences, Primary-care, 0302 clinical medicine, QUALITY-OF-LIFE, Health care, Global health, Medicine, Immunology and Allergy, 030223 otorhinolaryngology, Child, Animals, Asthma, Clinical Trials as Topic, Europe, Humans, Practice Guidelines as Topic, Rhinitis, Allergic, Perennial, Rhinitis, Allergic, Seasonal, World Health Organization, Persistent types, media_common, Rhinitis, PERSISTENT TYPES, PRIMARY-CARE, Effective primary care and public health [NCEBP 7], 3. Good health, GRADE, medicine.medical_specialty, Immunology, MEDLINE, World-health-organization, CONTROLLED-TRIAL, CLASSIFICATION, 03 medical and health sciences, Quality of life (healthcare), Allergic, EUROPEAN-UNION, rhinitis, Rhinitis, asthma, Allergic Rhinitis and its Impact on Asthma, allergy, GRADE, MANAGEMENT, media_common.cataloged_instance, Controlled-trial, Allergic Rhinitis and its Impact on Asthma, allergy, asthma, European union, Seasonal, business.industry, Guideline, medicine.disease, Perennial, 2008 UPDATE, Family medicine, Quality-of-life, Clinical Medicine, business, 030215 immunology
Abstract

Stallergenes ALK-Abello European Academy of Allergy and Clinical Immunology (EAACI) MSD Novartis Nycomed/Takeda PHADIA/Thermo Fischer 3M AstraZeneca GlaxoSmithKline Merck Frosst Altair Amgen Asmacure Boehringer-Ingelheim Genentech Pharmaxis Schering Wyeth Ache Brazilian Research Council Fundacao de Amparo a Pesquisa da Bahia Fundacao Ciencia e Tecnologia Sociedade Portuguesa de Alergologia e Immunologia Clinica Abdi Ibrahim OrionPharma Nasonebs Merck McNeal Chiesi Nycomed Air Liquid Healthcare Mundipharma Almirall Kyorin Teva UK National Health Service Aerocrine AKL Ltd PREDICTA Swiss National Science Foundation MeDALL Global Allergy and Asthma European Network (GA 2LEN) Christine Kuthe Center for Allergy Research and Education Faes Farma Bial Johnson Johnson Sanofi HAD treasurer Innovative Medicine Initiative (EU) Helse Sor-Ost RHF (Southern and Eastern Norway Regional Health Authority) MEDA Alcon ISTA Thermo-Fisher Airsonett Medical Research Council Moulton Charitable Trust AB Science Canadian Institutes for Health Research AllerGen NCE Merck/Schering-Plough Circassia University Hospital Medical School of Universidad Autonoma de Nuevo Leon, Mexico Children's Research Foundation (Ireland) Danone Food Standards Agency (United Kingdom) European Union (EU) DTG Netherlands Asthma Foundation Merck-Sharp-Dohme, Mexico Allerquim Mexico Abbott Apotex HRA MedImmune Schering-Plough Proctor Gamble Sunovion (Sepracor) Phadia Servier CSC JohnsonJohnson Oxygen Plus New Medics European Respiratory Society Societe de Pneumologie de Langue Francaise Asthma Ministry of Health, Welfare, and Labor Altana Takeda UCB Uriach advisory board NAPP Royal College of GPs Clinical Champion in Allergy Agency for Healthcare Research and Quality (AHRQ) AnseII Bayer Schering OST Fujisawa IHAL Henkel Allergic rhinitis (AR) and asthma represent global health problems for all age groups. Asthma and rhinitis frequently coexist in the same subjects. Allergic Rhinitis and its Impact on Asthma (ARIA) was initiated during a World Health Organization workshop in 1999 (published in 2001). ARIA has reclassified ARas mild/moderate-severe and intermittent/persistent. This classification closely reflects patients' needs and underlines the close relationship between rhinitis and asthma. Patients, clinicians, and other health care professionals are confronted with various treatment choices for the management of AR. This contributes to considerable variation in clinical practice, and worldwide, patients, clinicians, and other health care professionals are faced with uncertainty about the relative merits and downsides of the various treatment options. in its 2010 Revision, ARIA developed clinical practice guidelines for the management of AR and asthma comorbidities based on the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system. ARIA is disseminated and implemented in more than 50 countries of the world. Ten years after the publication of the ARIAWorld Health Organization workshop report, it is important to make a summary of its achievements and identify the still unmet clinical, research, and implementation needs to strengthen the 2011 European Union Priority on allergy and asthma in children. (J Allergy Clin Immunol 2012;130:1049-62.) Kryolan Leti MSO Procter and Gamble Sanofi-Aventis Scientific Advisory Board for the German Society for Allergy and Clinical Immunology German Federal Ministry of Consumer Protection European Centre for Allergy Research Foundation (ECARF) Hop Arnaud Villeneuve, Dept Resp Dis, Univ Hosp, Montpellier, France INSERM, U1018, CESP Ctr Res Epidemiol & Populat Hlth, Resp & Environm Epidemiol Team, Villejuif, France McMaster Univ, Dept Clin Epidemiol & Biostat & Med, Hamilton, ON, Canada Med Univ Warsaw, Dept Prevent Environm Hazards & Allergol, Warsaw, Poland Univ Hosp Montpellier, Hop Arnaud Villeneuve, INSERM, U657, Montpellier, France Catholic Univ, Fac Med, Res Ctr Resp Med CIMER, Cordoba, Argentina Univ Genoa, Sch Specializat, Genoa, Italy Univ Ghent, Dept Otorhinolaryngol, Upper Airways Res Lab, B-9000 Ghent, Belgium CNR, Inst Translat Pharmacol, Rome, Italy Univ Naples 2, Naples, Italy Univ Laval, Inst Univ Cardiol & Pneumol Quebec, Quebec City, PQ, Canada Univ Genoa, Dept Internal Med, DIMI, I-16126 Genoa, Italy Creighton Univ, Dept Med, Div Allergy & Immunol, Omaha, NE 68178 USA Univ Fed Bahia, ProAR Nucleo Excelencia Asma, Salvador, BA, Brazil CNPq, Salvador, BA, Brazil Univ Amsterdam, Dept Otorhinolaryngol, NL-1012 WX Amsterdam, Netherlands Univ Amsterdam, Acad Med Ctr, Dept Otorhinolaryngol, NL-1105 AZ Amsterdam, Netherlands Univ Porto, Sch Med, Dept Hlth Informat & Decis Sci, P-4100 Oporto, Portugal Univ Porto, Sch Med, CINTESIS, P-4100 Oporto, Portugal Hosp S Joao & Inst, Dept Allergy, Oporto, Portugal Hosp CUF Porto, Oporto, Portugal Erasmus MC, Dept Internal Med, Sect Allergol, Rotterdam, Netherlands Univ Washington, Sch Med, Seattle, WA USA Helsinki Univ Hosp, Dept Allergy, Skin & Allergy Hosp, Helsinki, Finland GARD ARIA Coordinator, Geneva, Switzerland Med Univ Lodz, Dept Internal Med Asthma & Allergy, Barlicki Univ Hosp, Lodz, Poland Univ S Florida, Coll Med, Dept Internal Med, Div Allergy & Immunol, Tampa, FL 33612 USA James A Haley Vet Hosp, Tampa, FL USA Univ Oslo, Oslo Univ Hosp, Dept Paediat, Oslo, Norway CIBERES, IDIBAPS, Hosp Clin, Rhinol Unit,ENT Dept, Barcelona, Spain CIBERES, IDIBAPS, Hosp Clin, Smell Clin,ENT Dept, Barcelona, Spain Univ Chicago, Dept Otolaryngol Head & Neck Surg, Chicago, IL 60637 USA Alfred Hosp, Dept Allergy Immunol & Resp Med, Melbourne, Vic, Australia Monash Univ, Melbourne, Vic 3004, Australia Teikyo Univ, Sch Med, Dept Med, Div Resp Med & Allergol, Tokyo 173, Japan EFA European Federat Allergy & Airways Dis Patien, Brussels, Belgium Univ Athens, Dept Allergy, Pediat Clin 2, Athens, Greece Nippon Med Sch, Bunkyo Ku, Tokyo 113, Japan Univ Aberdeen, Dept Primary Care Resp Med, Aberdeen, Scotland Woodbrook Med Ctr, Loughborough, Leics, England Univ Edinburgh, Edinburgh, Midlothian, Scotland Univ Manitoba, Fac Med, Winnipeg, MB, Canada NIAID, Bethesda, MD 20892 USA Univ N Carolina, Sch Pharm, Chapel Hill, NC USA Celal Bayar Univ, Sch Med, Dept Pulmonol, Manisa, Turkey Allergy & Asthma Inst, Islamabad, Pakistan Med Univ Graz, Dept Dermatol, Graz, Austria Showa Univ, Sch Med, Div Allergol & Resp Med, Tokyo 142, Japan Transylvania Univ, Fac Med, Brasov, Romania Int Union TB & Lung Dis Union, Paris, France Univ Zurich, Swiss Inst Allergy & Asthma Res SIAF, Davos, Switzerland Minist Hlth, Publ Hosp Med Serv, Antananarivo, Madagascar INSERM, EPAR U707, Paris, France Univ Paris 06, EPAR, UMR S, Paris, France Hosp Quiron Bizkaia, Dept Allergy & Immunol, Erandio Bilbao, Spain Univ Cape Town, Dept Med, Fac Hlth Sci, Div Pulmonol, ZA-7925 Cape Town, South Africa WHO, Collaborating Ctr Asthma & Rhinitis, Montpellier, France Univ Modena & Reggio Emilia, Dept Oncol Hematol & Resp Dis, Modena, Italy Ctr Hosp Univ Rabta, Serv Pneumol Allergol, Tunis, Tunisia Univ Amsterdam, Acad Med Ctr, Dept Pulmonol, NL-1105 AZ Amsterdam, Netherlands Hop Mami, Ariana, Tunisia Bangladesh Lung Fdn, Dhaka, Bangladesh Natl Inst Dis Chest & Hosp, Dhaka, Bangladesh Charite, Dept Dermatol, Allergy Ctr Charite, D-13353 Berlin, Germany Univ Med Ctr, Dept Dermatol & Allergy, Bonn, Germany Odense Univ Hosp, Dept Dermatol, DK-5000 Odense, Denmark Odense Univ Hosp, Allergy Ctr, DK-5000 Odense, Denmark Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA Univ Verona, Dept Paediat, I-37100 Verona, Italy Univ Laval, Fac Med, Quebec City, PQ G1K 7P4, Canada Hop Malbaie, La Malbaie, PQ, Canada Univ Leicester, Inst Lung Hlth, Leicester LE1 7RH, Leics, England Royal Brompton Hosp, Dept Paediat Resp Med, London SW3 6LY, England Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Sect Allergy & Clin Immunol, London, England Ctr Med Docente La Trinidad Caracas, Dept Immunol, Caracas, Venezuela Univ Austral Chile, Fac Med, Dept Pediat, Valdivia, Chile Univ Fed Sao Joao del Rei, Hlth Sci Ctr, Hlth Sci Postgrad Program, Divinopolis, Brazil Univ Cartagena, Immunol Res Inst, Cartagena de Indias, Colombia So Calif Res, Mission Viejo, CA USA Metropolitan Univ Barranquilla, Allergy & Immunol Lab, Barranquilla, Colombia IRCCS San Raffaele Pisana, Rome, Italy Univ Cattolica Sacro Cuore, Dept Thorac Surg, Rome, Italy Leiden Univ, Med Ctr, Dept Publ Hlth & Primary Care, Leiden, Netherlands Capital Inst Pediat, Asthma Clin, Natl Cooperat Grp Pediat Res Asthma, Beijing, Peoples R China Capital Inst Pediat, Educ Ctr, Beijing, Peoples R China Ctr Asthma Res & Educ, Beijing, Peoples R China Hop Arnaud Villeneuve, Univ Hosp, Allergy Unit, Montpellier, France Univ Hosp, Dept Allergol, Sch Med CEU San Pablo Madrid, Madrid, Spain Georgian Natl Univ, AIETI Med Sch, SEU Clin, Med Ctr, Tbilisi, Rep of Georgia Univ Genoa, Dept Internal Med, IRCCS Azienda Osped Univ San Martino, I-16126 Genoa, Italy Univ Montpellier I, Primary Care Dept, Montpellier, France Nova SE Univ, Coll Osteopath Med, Davie, FL USA Univ Manchester, Manchester, Lancs, England Aarhus Univ Hosp, Dept Resp Dis, DK-8000 Aarhus, Denmark Tech Univ Munich, Dept Dermatol & Allergy Biederstein, Munich, Germany TUM, Div Environm Dermatol, Munich, Germany TUM, Allergy Helmholtz Ctr, Munich, Germany Univ Hosp Strasbourg, Chest Dis Dept, Div Pulmonol Asthma & Allergol, Strasbourg, France Univ Med & Pharm Iuliu Hatieganu, Dept Allergy, Med Clin 3, Romanian Soc Allergy & Clin Immunol, Cluj Napoca, Romania McMaster Univ, AllerGen NCE, Dept Med, Hamilton, ON, Canada McMaster Univ, AllerGen NCE, Michael G DeGroote Sch Med, Div Clin Immunol & Allergy,Fac Hlth Sci, Hamilton, ON, Canada Univ Versailles St Quentin, Hop Foch, UPRES EA 220, Suresnes, France Ctr Hosp Reg Annecy, Serv Pneumol, Annecy, France Univ Ss Cyril & Methodius, Univ Clin Pulmonol & Allergy, Skopje, Macedonia Georgia Hlth Sci Univ, Augusta, GA USA Ctr Hosp Univ Beni Messous, Serv Pneumoallergol, Algiers, Algeria Vilnius Univ, Fac Med, Collaborating Ctr GA2LEN, Vilnius, Lithuania Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA Ain Shams Univ, Childrens Hosp, Pediat Allergy & Immunol Unit, Cairo, Egypt Egyptian Soc Pediat Allergy & Immunol, Cairo, Egypt Soc Marocaine Malad Resp, Casablanca, Morocco Ctr Resp Dis & Allergy, Casablanca, Morocco Vilnius Univ, Fac Med, Vilnius, Lithuania Univ Milan, Sch Med, Melloni Hosp, Milan, Italy Educ Hlth, Warwick, England Dokkyo Med Univ, Mibu, Tochigi, Japan WHO, Country Off Georgia, Tbilisi, Rep of Georgia Clin Ricardo Palma, Lima, Peru Univ Nuevo Leon UANL, Hosp Univ, Fac Med, Monterrey, Mexico Ctr Allergy & Immunol, Tbilisi, Rep of Georgia Clin Hosp Univ Chile, Dept Med, Immunol & Allergol Div, Santiago, Chile Univ Hosp Leuven, Dept Otorhinolaryngol Head & Neck Surg, Louvain, Belgium Cent Reg Denmark, Ctr Publ Hlth & Qual Improvement, Aarhus, Denmark Allergy Ctr Vienna W, Vienna, Austria Natl Univ Ireland Univ Coll Cork, Dept Paediat & Child Hlth, Cork, Ireland Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England Univ Paris 11, Serv Pneumol, Hop Antoine Beclere, AP HP,INSERM,U999, Clamart, France Salvador Univ, Sch Med, Dept Immunol, Buenos Aires, DF, Argentina Univ St Andrews, St Andrews, Fife, Scotland Univ Paris, APHP, Ctr Asthme & Allergies, Grp Hosp Trousseau La Roche Guyon, F-75252 Paris, France Hacettepe Univ, Sch Med, Pediat Allergy & Asthma Unit, Ankara, Turkey George Washington Univ, Sch Med, Washington, DC USA Inst Asthma & Allergy, Chevy Chase, MD USA Hacettepe Univ Hosp, Dept Chest Dis, Adult Allergy Unit, Ankara, Turkey Charite, Inst Social Med Epidemiol & Hlth Econ, D-13353 Berlin, Germany McMaster Univ, Hamilton, ON, Canada Hotel Dieu France, Serv Pneumol & Reanimat Med, Beirut, Lebanon Univ St Joseph, Fac Med, Beirut, Lebanon Natl Med Ctr, Seoul, South Korea Seoul Natl Univ, Seoul, South Korea Korea Asthma Allergy Fdn, Seoul, South Korea Ctr Hosp Univ, Serv Malad Resp, Abidjan, Cote Ivoire Univ Groningen, Univ Med Ctr Groningen, GRIAC Res Inst, Beatrix Childrens Hosp,Dept Pediat Pulmonol & Ped, Groningen, Netherlands Med Univ Lodz, Dept Immunol Rheumatol & Allergy, Lodz, Poland Karolinska Inst, Dept Clin Sci & Educ, Stockholm, Sweden Karolinska Inst, Sachs Childrens Hosp, Stockholm, Sweden Vilnius Univ, Ctr Pulmonol & Allergol, Vilnius, Lithuania Vilnius Univ Hosp Santariskiu Klinikos, Vilnius, Lithuania Hosp Med Sur, Dept Allergy, Mexico City, DF, Mexico Univ Med & Pharm, Thanh Pho Ho Chi Minh, Vietnam Hop Sacre Coeur Montreal, Montreal, PQ, Canada Univ Montreal, Montreal, PQ, Canada Guangzhou Med Univ, Affiliated Hosp 1, State Key Lab Resp Dis, Guangzhou, Guangdong, Peoples R China Univ Tennessee, Coll Med, Memphis, TN USA Univ Dundee, Ninewells Hosp, Asthma & Allergy Res Grp, Dundee, Scotland Dubai Hlth Author, Sharjah, U Arab Emirates Univ Sharjah, Sharjah, U Arab Emirates Univ Mississippi, Med Ctr, Div Clin Immunol & Allergy, Jackson, MS 39216 USA Univ Arizona, Coll Med, Arizona Resp Ctr, Tucson, AZ USA Univ Arizona, Inst BIO5, Tucson, AZ USA Shahid Beheshti Univ Med Sci, NRITLD, Tehran, Iran Shahid Beheshti Univ Med Sci, Chron Resp Dis Res Ctr, Tehran, Iran Charite, Dept Dermatol & Allergy, D-13353 Berlin, Germany Maputo Cent Hosp, Dept Peadiat, Maputo, Mozambique Eduardo Mondlane Univ, Fac Med, Maputo, Mozambique Childrens Hosp La Fe, Unit Pediat Allergy & Pneumol, Valencia, Spain Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Stockholm, Sweden Univ Calif San Diego, Allergy & Asthma Med Grp, San Diego, CA 92103 USA Univ Calif San Diego, Res Ctr, San Diego, CA 92103 USA IMSS, Dept Allergy & Clin Immunol, Ctr Med Nacl Siglo 21, Mexico City, DF, Mexico Univ Aachen, Dept Dermatol, Aachen, Germany Inst Pneumol Marius Nasta, Bucharest, Romania Tishreen Univ, Sch Med, Dept Internal Med, WHO EMRO Collaborating Ctr Training & Res Chron R, Latakia, Syria CUF Descobertas Hosp, Immunoallergy Dept, Lisbon, Portugal Univ Padua, Dept Pediat, Food Allergy Referral Ctr Veneto Reg, Padua, Italy Mustapha Hosp, Algiers, Algeria Sci Ctr Childrens Hlth RAMS, Moscow, Russia Hosp Hospitaller Bros Buda, Budapest, Hungary Charite, Allergie Ctr Charite ECARF, Dept Dermatol Venerol & Allergy, D-13353 Berlin, Germany German Red Cross Hosp Westend, Berlin, Germany Jagiellonian Univ, Sch Med, Dept Pulmonol, Krakow, Poland Kinshasa Univ, ENT Dept, Kinshasa, Zaire Chiba Univ Hosp, Dept Otorhinolaryngol, Chiba, Japan Nippon Med Sch, Dept Otolaryngol, Bunkyo Ku, Tokyo 113, Japan Ctr Hosp Univ Pediat Charles de Gaulle, Ouagadougou, Burkina Faso Marmara Univ, Div Pediat Allergy & Immunol, Istanbul, Turkey Mem Hlth Grp, Istanbul, Turkey Charles Univ Prague, Fac Med Plzen, Dept Immunol & Allergol, Prague, Czech Republic MESSERLI Res Inst, Vienna, Austria Med Univ Vienna, Univ Vet Med Vienna, Vienna, Austria Univ Vienna, Vienna, Austria Ajou Univ, Sch Med, Suwon 441749, South Korea NICE, Paris, France Soc Pneumol Langue Francaise, Paris, France Krankenhaus Hietzing, Karl Landsteiner Inst Expt & Clin Pneumol, Dept Pulm Med, Vienna, Austria Alexanders Univ Hosp, Clin Allergy & Asthma, Sofia, Bulgaria Univ Groningen, Univ Med Ctr Groningen, GRIAC Res Inst, Dept Pulmonol, Groningen, Netherlands Univ Cape Town, Lung Inst, ZA-7925 Cape Town, South Africa Groote Schuur Hosp, ZA-7925 Cape Town, South Africa Leiden Univ, Dept Pulmonol, Med Ctr, Leiden, Netherlands Grosshansdorf Clin, Grosshansdorf, Germany Hop Prive Athis Mons, Serv Pneumol, Athis Mons, France Helsinki Univ Hosp, Dept Dermatol, Skin & Allergy Hosp, Helsinki, Finland Tech Univ Munich, CKCARE, Dept Dermatol Allergy Biederstein, Munich, Germany Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA Med Univ Silesia, Dept & Clin Internal Dis Allergol & Clin Immunol, Katowice, Poland Complesso Integrato Columbus, Allergy Unit, Rome, Italy IRCCS Oasi Maria SS, Troina, Italy Son Pisa Primary Care Ctr, IB Salut Balear Hlth Serv, Int Primary Care Resp Grp, Palma de Mallorca, Spain Hosp Luz, Immunoallergy Dept, Lisbon, Portugal Univ Missouri, Kansas City Sch Med, Kansas City, MO 64110 USA Childrens Mercy Hosp, Kansas City, MO USA Emek Med Ctr, Afula, Israel Technion Israel Inst Technol, Rappaport Fac Med, Haifa, Israel Ctr Med Docente La Trinidad, Dept Allergy & Clin Immunol, Caracas, Venezuela UCL, Royal Natl TNE Hosp, London, England Univ Zurich Hosp, Dept Dermatol, Allergy Unit, CH-8091 Zurich, Switzerland Univ Edinburgh, Sch Med, Ctr Populat Hlth Sci, Allergy & Resp Res Grp, Edinburgh, Midlothian, Scotland Universidade Federal de São Paulo, Dept Pediat, Div Allergy Clin Immunol & Rheumatol, São Paulo, Brazil Natl Ctr Cardiol & Internal Med, Bishkek, Kyrgyzstan Ctr ACI Immunoflow, Czech Initiat Asthma, Prague, Czech Republic GAAPP, Vienna, Austria Ctr Res Environm Epidemiol CREAL, Barcelona, Spain Pontificia Univ Catolica RGS, Sch Med, Porto Alegre, RS, Brazil Univ Nevada, Sch Med, Reno, NV 89557 USA Hosp Mar, Municipal Inst Med Res IMIM, Barcelona, Spain CIBER Epidemiol & Salud Publ CIBERESP, Barcelona, Spain Univ Pompeu Fabra UPF, Barcelona, Spain Jagiellonian Univ, Coll Med, Krakow, Poland Coimbra Univ Hosp, Immunoallergy Dept, Coimbra, Portugal Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA Finnish Inst Occupat Hlth, Helsinki, Finland Univ Laval, Fac Med, Dept Obstet & Gynecol, Laval, PQ, Canada Med Univ Vienna, Christian Doppler Lab Allergy Res, Div Immunopathol, Dept Pathophysiol & Allergy Res,Ctr Pathophysiol, Vienna, Austria Hosp Clin Barcelona, Dept Pneumol, Allergy Unit, Immunoallergia Resp Clin, Barcelona, Spain IDIBAPS, Barcelona, Spain CIBERES, Barcelona, Spain Univ Paris 13, Bobigny, France Avicenne Hosp, AP HP, Bobigny, France Vilnius Univ, Fac Med, Dept Paediat, Vilnius, Lithuania Lithuanian Natl Council Childs Hlth, Vilnius, Lithuania Terveystalo Turku, Allergy Clin, Turku, Finland Univ Turku, Dept Lung Dis & Clin Immunol, Turku, Finland Univ Ghent, Dept Otorhinolaryngol, B-9000 Ghent, Belgium Catholic Univ Louvain, Univ Hosp Mt Godinne, Yvoir, Belgium Radboud Univ Nijmegen, Med Ctr, Dept Primary & Community Care, NL-6525 ED Nijmegen, Netherlands Siriraj Hosp, Fac Med, Dept Pediat, Bangkok, Thailand CNR, IBIM, Palermo, Italy Clin Physiol IFC, Pisa, Italy Natl Univ Singapore, Yong Loo Lin Sch Med, Singapore 117595, Singapore Floridsdorf Allergy Ctr FAZ, Vienna, Austria Med Univ Vienna, Dept Dermatol, DIAID, Vienna, Austria Bradford Teaching Hosp Fdn Trust, Bradford Inst Hlth Res, Bradford, W Yorkshire, England Olmsted Med Ctr, Dept Res, Rochester, MN USA Univ Minnesota, Dept Family & Community Hlth, Rochester, MN USA Harvard Univ, Sch Publ Hlth, Cyprus Int Inst Environm & Publ Hlth Assoc, Limassol, Cyprus Cyprus Univ Technol, Limassol, Cyprus Univ Cape Town, Red Cross War Mem Childrens Hosp, Dept Paediat & Child Hlth, ZA-7925 Cape Town, South Africa Catholic Univ Cordoba, Sch Med, Dept Otorhinolaryngol, Cordoba, Argentina Guangzhou Med Univ, Guangzhou Inst Resp Dis, Guangzhou, Guangdong, Peoples R China Guangzhou Med Univ, State Key Lab Resp Dis, Guangzhou, Guangdong, Peoples R China Univ Clin Resp & Allerg Dis, Golnik, Slovenia Charite, Network Excellence, Global Allergy & Asthma European Network GA2LEN, D-13353 Berlin, Germany Universidade Federal de São Paulo, Dept Pediat, Div Allergy Clin Immunol & Rheumatol, São Paulo, Brazil Web of Science

Published
2012
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34. B-Cell Epitopes in NTS-DBL1α of PfEMP1 Recognized by Human Antibodies in Rosetting Plasmodium falciparum

Author

Karin Blomqvist, Letusa Albrecht, Fabio Luiz D'Alexandri, Markus Maurer, Kirsten Moll, Davide Valentini, Davide Angeletti, Mats Wahlgren, Karolinska Inst, Karolinska Univ Hosp, Universidade Estadual de Campinas (UNICAMP), and Universidade Federal de São Paulo (UNIFESP)

Subjects
Models, Molecular, Plasmodium, Erythrocytes, Microarray, Molecular Sequence Data, Plasmodium falciparum, Protozoan Proteins, lcsh:Medicine, Antibodies, Protozoan, Virulence, Epitope, law.invention, law, Parasite Groups, parasitic diseases, Cell Adhesion, medicine, Humans, Amino Acid Sequence, lcsh:Science, Conserved Sequence, Multidisciplinary, biology, lcsh:R, Biology and Life Sciences, Biological activity, biology.organism_classification, Virology, Protein Structure, Tertiary, Red blood cell, medicine.anatomical_structure, Recombinant DNA, biology.protein, Epitopes, B-Lymphocyte, lcsh:Q, Parasitology, Antibody, Apicomplexa, Research Article
Abstract

Swedish Research Council (VR) Swedish Academy of Sciences (KVA, Soderberg Foundation) Karolinska Institutet-DPA EU Network of Excellence EviMalar Plasmodium falciparum is the most lethal of the human malaria parasites. the virulence is associated with the capacity of the infected red blood cell (iRBC) to sequester inside the deep microvasculature where it may cause obstruction of the blood-flow when binding is excessive. Rosetting, the adherence of the iRBC to uninfected erythrocytes, has been found associated with severe malaria and found to be mediated by the NTS-DBL1 alpha-domain of Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1). Here we show that the reactivity of plasma of Cameroonian children with the surface of the FCR3S1.2-iRBC correlated with the capacity to disrupt rosettes and with the antibody reactivity with a recombinant PfEMP1 (NTS-DBL1 alpha of IT4(var60)) expressed by parasite FCR3S1.2. the plasma-reactivity in a microarray, consisting of 96 overlapping 15-mer long peptides covering the NTS-DBL1 alpha domain from IT4var60 sequence, was compared with their capacity to disrupt rosettes and we identified five peptides where the reactivity were correlated. Three of the peptides were localized in subdomain-1 and 2. the other two peptide-sequences were localized in the NTS-domain and in subdomain-3. Further, principal component analysis and orthogonal partial least square analysis generated a model that supported these findings. in conclusion, human antibody reactivity with short linear-peptides of NTS-DBL1 alpha of PfEMP1 suggests subdomains 1 and 2 to hold anti-rosetting epitopes recognized by anti-rosetting antibodies. the data suggest rosetting to be mediated by the variable areas of PfEMP1 but also to involve structurally relatively conserved areas of the molecule that may induce biologically active antibodies. Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden Karolinska Inst, Dept Lab Med, Therapeut Immunol TIM, Stockholm, Sweden Karolinska Univ Hosp, CAST, Huddinge, Sweden Univ Estadual Campinas, Dept Biochem, Campinas, SP, Brazil Universidade Federal de São Paulo, EPM, São Paulo, Brazil Web of Science

Published
2014
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35. Dopaminergic Neuronal Imaging in Genetic Parkinson's Disease: Insights into Pathogenesis

Author

Oswaldo Lorenzo-Betancor, Andrea Varrone, Henry Houlden, Pau Pastor, Paolo Barone, Orlando Graziani Povoas Barsottini, Thomas Foltynie, José Matías Arbelo, Marcelo Q. Hoexter, Giovanni Cossu, André Carvalho Felício, Kailash P. Bhatia, Joanna Herrera, Alisdair McNeill, Vincenzo Bonifati, Concepcion Isla, Sabina Pappatà, Anthony H.V. Schapira, Ruey-Meei Wu, Patricia de Carvalho Aguiar, Niccolo E. Mencacci, Maria Teresa Pellecchia, Henrique Ballalai Ferraz, Kai-Yuan Tzen, Pietro Cortelli, Rodrigo A. Bressan, Laura Silveria-Moriyama, Sevasti Bostantjopoulou, Andrew J. Lees, A. McNeill, R. Wu, K. Tzen, P. C. Aguiar, J. M. Arbelo, P. Barone, K. Bhatia, O. Barsottini, V. Bonifati, S. Bostantjopoulou, R. Bressan, G. Cossu, P. Cortelli, A. Felicio, H. B. Ferraz, J. Herrera, H. Houlden, M. Hoexter, C. Isla, A. Lee, O. Lorenzo-Betancor, N. E. Mencacci, P. Pastor, S. Pappata, M. T. Pellecchia, L. Silveria-Moriyama, A. Varrone, T. Foltynie, A. H. V, Clinical Genetics, UCL, Birmingham Womens Hosp, Natl Taiwan Univ Hosp, Hosp Israelita Albert Einstein, Hosp Univ Insular Gran Canaria, Univ Salerno, Universidade Federal de São Paulo (UNIFESP), Erasmus MC, Aristotle Univ Thessaloniki, Gen Hosp S Michele AOB G Brotzu, Univ Bologna, UCL Inst Neurol, Univ Navarra, CNR, and Karolinska Inst

Subjects
Male, Pathology, Parkinson's disease, Caudate nucleus, lcsh:Medicine, pathology, Female, Genotype, Humans, Male, Neuroimaging, Parkinson Disease, genetics/pathology, Positron-Emission Tomography, Putamen, Parkin, Diagnostic Radiology, Cohort Studies, pathology, Cohort Studies, Demography, Dopamine Plasma Membrane Transport Protein, chemistry.chemical_compound, 0302 clinical medicine, Autosomal Recessive, Medicine, lcsh:Science, Neuropathology, 0303 health sciences, Movement Disorders, Multidisciplinary, Putamen, Parkinson Disease, LRRK2, Neurology, Autosomal Dominant, Female, Radiology, Research Article, Adult, medicine.medical_specialty, Genotype, Neuroimaging, PINK1, 03 medical and health sciences, Diagnostic Medicine, Humans, Demography, 030304 developmental biology, Clinical Genetics, Tomography, Emission-Computed, Single-Photon, Alpha-synuclein, Dopamine Plasma Membrane Transport Proteins, metabolism, Dopaminergic Neuron, business.industry, Dopaminergic Neurons, lcsh:R, Personalized Medicine, medicine.disease, nervous system diseases, chemistry, Anatomical Pathology, Positron-Emission Tomography, lcsh:Q, Emission-Computed, Nuclear Medicine, Caudate Nucleus, Adult, Caudate Nucleu, pathology, Tomography, business, Neuroscience, Glucocerebrosidase, 030217 neurology & neurosurgery, Single-Photon
Abstract

Wellcome Trust/MRC Joint Call in Neurodegeneration award United Kingdom Medical Research Council Wellcome Trust Parkinson's Disease UK Kattan Trust Objectives: To compare the dopaminergic neuronal imaging features of different subtypes of genetic Parkinson's Disease.Methods: A retrospective study of genetic Parkinson's diseases cases in which DaTSCAN (123I-FP-CIT) had been performed. Specific non-displaceable binding was calculated for bilateral caudate and putamen for each case. the right: left asymmetry index and striatal asymmetry index was calculated.Results: Scans were available from 37 cases of monogenetic Parkinson's disease (7 glucocerebrosidase (GBA) mutations, 8 alpha-synuclein, 3 LRRK2, 7 PINK1, 12 Parkin). the asymmetry of radioligand uptake for Parkinson's disease with GBA or LRRK2 mutations was greater than that for Parkinson's disease with alpha synuclein, PINK1 or Parkin mutations.Conclusions: the asymmetry of radioligand uptake in Parkinsons disease associated with GBA or LRRK2 mutations suggests that interactions with additional genetic or environmental factors may be associated with dopaminergic neuronal loss. UCL, Dept Clin Neurosci, Inst Neurol, London, England Birmingham Womens Hosp, Reg Genet Unit, Dept Clin Genet, Birmingham, W Midlands, England Natl Taiwan Univ Hosp, Coll Med, Dept Neurol, Taipei, Taiwan Natl Taiwan Univ Hosp, Coll Med, Dept Nucl Med, Taipei, Taiwan Hosp Israelita Albert Einstein, Inst Israelita Ensino & Pesquisa Albert Einstein, São Paulo, Brazil Hosp Univ Insular Gran Canaria, Dept Neurol, Parkinsons & Movement Disorders Unit, Las Palmas Gran Canaria, Spain Univ Salerno, Ctr Neurodegenerat Dis, Salerno, Fisciano Provin, Italy UCL, Inst Neurol, Sobell Dept Motor Sci, London, England Universidade Federal de São Paulo, Dept Neurol, São Paulo, Brazil Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands Aristotle Univ Thessaloniki, G Papanikolaou Hosp, Dept Neurol 3, GR-54006 Thessaloniki, Greece Gen Hosp S Michele AOB G Brotzu, Neurol Serv, Cagliari, Italy Gen Hosp S Michele AOB G Brotzu, Stroke Unit, Cagliari, Italy Univ Bologna, Dept Biomed & Neuromotor Sci, Bologna, Italy Universidade Federal de São Paulo UNIFESP, EPM, Div Movement Disorders, São Paulo, Brazil UCL Inst Neurol, Dept Mol Neurosci, London, England Univ Navarra, Div Neurosci, Ctr Appl Med Res, Neurogenet Lab, E-31080 Pamplona, Spain CNR, Inst Biostruct & Bioimaging, I-80125 Naples, Italy Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden Universidade Federal de São Paulo, Dept Neurol, São Paulo, Brazil Universidade Federal de São Paulo UNIFESP, EPM, Div Movement Disorders, São Paulo, Brazil Wellcome Trust/MRC Joint Call in Neurodegeneration award: WT089698 United Kingdom Medical Research Council: G1001983 Web of Science

Published
2013
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