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Your search keyword '"David Altshuler"' showing total 145 results
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145 results on '"David Altshuler"'

1. Exercise improves health-related quality of life sleep and fatigue domains in adult high- and low-grade glioma patients

Author

Zachary Miklja, Shawn L. Hervey-Jumper, Sean R. Smith, David Altshuler, Nicolette Gabel, and Lin Wang

Subjects
Adult, Male, Oncology, medicine.medical_specialty, Population, Article, Quality of life, Internal medicine, Glioma, medicine, Humans, education, Exercise, Fatigue, Neurorehabilitation, Sleep disorder, education.field_of_study, business.industry, Perioperative, medicine.disease, Sleep in non-human animals, Distress, Quality of Life, Female, Sleep, business
Abstract

PURPOSE: The impact of exercise on health-related quality of life (HRQOL) in patients with glioma remains unknown. We hypothesized that glioma patients with low exercise tolerance experience more distress in HRQOL sleep and fatigue domains than patients with high tolerance to exercise. METHODS: Thirty-eight male and female patients with low- or high-grade glioma treated at a single tertiary care institution participated. Patients completed a validated telephone survey to determine their exercise habits before and following diagnosis. An unpaired t-test was run to measure the interaction between exercise tolerances on HRQOL functional and impairment domains. RESULTS: Those with low pre-morbid physical activity levels had more distress in HRQOL sleep and fatigue domains. The effects were independent of plasma brain-derived neurotrophic factor (BDNF) levels and the degree of exercise did not appear to impact plasma BDNF in adult glioma patients. CONCLUSIONS: The aim of this study was to examine the significance of exercise habits on perioperative functional outcomes in patients with low-grade or high-grade glioma. We found that glioma patients with low tolerance to exercise had more sleep disturbances and greater fatigue than glioma patients with high tolerance to exercise. Furthermore, exercise tolerance in the adult glioma population does not appear to impact plasma BDNF secretion.

Published
2021

2. Vascular compromise in a torsed transposed ulnar nerve case in support of intravenous contrast administration

Author

Kara Gaetke Udager, David Altshuler, Yoav Morag, and Lynda C. Yang

Subjects
Intravenous contrast, medicine.medical_specialty, Blood-Nerve Barrier, business.industry, Vascular compromise, Torsion (gastropod), Peripheral Nervous System Diseases, medicine.disease, 030218 nuclear medicine & medical imaging, Peripheral, Surgery, body regions, 03 medical and health sciences, 0302 clinical medicine, Peripheral neuropathy, 030220 oncology & carcinogenesis, medicine, Humans, Radiology, Nuclear Medicine and imaging, business, Ulnar nerve, Ulnar Nerve, Preoperative imaging
Abstract

Nerve torsion is a recognized etiology in brachial and peripheral neuropathy. Vascular compromise of peripheral nerves is uncommon given their unique vascular supply. Preoperative imaging diagnosis of nerve torsion and vascular compromise can be made in some cases, which impacts treatment. We present a previously unreported case of long segment torsion and vascular compromise of the ulnar nerve following anterior subcutaneous transposition with a description of the imaging findings based on the unique structure of the nerve and the presence of a blood nerve barrier (BNB) and a discussion of the potential vulnerability of a transposed and torsed nerve.

Published
2021

3. Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author

Tove Fall, Anubha Mahajan, Dmitry Shungin, B. Balkau, Gerjan Navis, A. Metspalu, Anneli Pouta, Andrew A. Hicks, Ilja M. Nolte, Ian Ford, Aroon D. Hingorani, Stefan R Bornstein, Anuj Goel, Rona J. Strawbridge, Niek Verweij, Sarah H. Wild, Patricia B. Munroe, T.B. Harris, Jaana Lindström, Johnson Pcd., Nita G. Forouhi, Pierre Meneton, Patricia A. Peyser, Sarin A-P., Andrea Ganna, Timothy M. Frayling, Patrik K. E. Magnusson, Joanne M. Meyer, Yongmei Liu, Jeanette M. Stafford, Christian Herder, L Zudina, Maria G. Stathopoulou, May E. Montasser, Nicholas D. Hastie, Inês Barroso, Schwarz Peh., James B. Meigs, Perttu Salo, George Davey Smith, Gonneke Willemsen, Christopher J. Groves, Erik P A Van Iperen, M. A. Province, Veikko Salomaa, Naveed Sattar, Serena Sanna, Maria Dimitriou, Joop Jukema, Ulrika Krus, Albert V. Smith, Markku Laakso, James F. Wilson, George Nicholson, Loic Yengo, Tatijana Zemunik, Per Eriksson, Harold Snieder, Peter P. Pramstaller, Claudia Langenberg, R. Rauramaa, Alan R. Shuldiner, Pau Navarro, Veronique Vitart, Ross M. Fraser, Aaron Isaacs, C. Lecoeur, Jesper R. Gådin, Jackie F. Price, Letizia Marullo, L.F. Bielak, Sirkka Keinänen-Kiukaanniemi, Amélie Bonnefond, Michael Stumvoll, Alessia Faggian, Anke Tönjes, Tomohiro Tanaka, Wieland Kiess, Harry Campbell, Josée Dupuis, David Altshuler, João Fadista, Winfried März, G K Hovingh, Thomas Illig, Toby Johnson, H Grallert, Kari Stefansson, Reedik Mägi, Palmer Cna., de Geus Ejcn., Martina Müller-Nurasyid, Karen Kapur, Philippe Froguel, Dorret I. Boomsma, Anders Franco-Cereceda, Marcus E. Kleber, Boehnke M, Olga D. Carlson, Ozren Polasek, Andrew P. Morris, Alex S. F. Doney, Najaf Amin, Sara M. Willems, Vilmundur Gudnason, Jose C. Florez, Jeffery R. O'Connell, Nancy L. Pedersen, T. Saaristo, Wolffenbuttel Bhr., M. I. J. Uusitupa, Longda Jiang, Iva Miljkovic, James S. Pankow, Caroline Hayward, Hugh Watkins, Vasiliki Lagou, Johanna Kuusisto, Jaakko Tuomilehto, Alan F. Wright, Josephine M. Egan, Perry Jrb., C M van Duijn, Valeriya Lyssenko, Leif Groop, Stefania Bandinelli, Nigel W. Rayner, Tõnu Esko, Stela McLachlan, Momoko Horikoshi, Eric Boerwinkle, Rick Jansen, Richard N. Bergman, Gudmar Thorleifsson, Lyle J. Palmer, Vilmantas Giedraitis, Peter Kovacs, Nicholas J. Wareham, Luigi Ferrucci, N J Timpson, D Rybin, Anne U. Jackson, Tiinamaija Tuomi, Gonçalo R. Abecasis, Harst Pvd., Meena Kumari, Albert Hofman, Chiara Scapoli, Evelin Mihailov, Josine L. Min, Anders Hamsten, Hottenga J-J., Loos Rjf., Lars Lind, Ulf de Faire, Jaakko Kaprio, Guo Li, Beate St Pourcain, C Gieger, Amanda J. Bennett, Anna Ulrich, Nabila Bouatia-Naji, Satu Männistö, Antigone S. Dimas, Jarvelin M-R., Günther Silbernagel, F Karpe, A. Körner, David S. Siscovick, M Blüher, Rebecca J. Webster, Erik Ingelsson, Susan Campbell, Mika Kivimäki, Laura J. Rasmussen-Torvik, Heikki A. Koistinen, Sophie Visvikis-Siest, Bernhard O. Boehm, Inga Prokopenko, Ping An, Emmanouil T. Dermitzakis, Cecilia M. Lindgren, Kardia Slr., Richa Saxena, Igor Rudan, Richard M. Watanabe, Jian'an Luan, Marika Kaakinen, Shin S-Y., George Dedoussis, Panagiotis Deloukas, Mark I. McCarthy, Barbara Thorand, B.W.J.H. Penninx, Peter Vollenweider, Paul W. Franks, Leena Kinnunen, Markus Perola, Yvonne Boettcher, Timo A. Lakka, Nicole Soranzo, Stavroula Kanoni, Bakker Sjl., Winkelmann Br, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Institute of Genomics [Tartu, Estonia], University of Tartu, Vrije Universiteit Amsterdam [Amsterdam] (VU), Vrije Universiteit Medical Centre (VUMC), Helmholtz-Zentrum München (HZM), University of Cambridge [UK] (CAM), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Università degli Studi di Ferrara (UniFE), Boston University [Boston] (BU), VU University Medical Center [Amsterdam], University of Bristol [Bristol], Biomedical Sciences Research Centre Alexander Fleming [Vari, Greece] (BSRC), Imperial College London, Karolinska Institutet [Stockholm], Institute for Molecular Bioscience, University of Queensland [Brisbane], Statens Serum Institut [Copenhagen], Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Cardiovascular Research Institute Maastricht (CARIM), Maastricht University [Maastricht], MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, National Institute on Aging [Baltimore, MD, USA] (NIH), University of Michigan [Ann Arbor], University of Michigan System, University of Maryland School of Medicine, University of Maryland System, The University of Western Australia (UWA), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Wake Forest University, National Institute for Health and Welfare [Helsinki], The Wellcome Trust Sanger Institute [Cambridge], University of Iceland [Reykjavik], University of Washington [Seattle], University of Groningen [Groningen], University of Glasgow, William Harvey Research Institute, Barts and the London Medical School, Université de Lausanne (UNIL), deCODE genetics [Reykjavik], Northwestern University Feinberg School of Medicine, Uppsala Universitet [Uppsala], University of Edinburgh, Medical Faculty [Mannheim], University of Graz, Ludwig-Maximilians-Universität München (LMU), Johannes Gutenberg - Universität Mainz (JGU), Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki-University of Helsinki, Umeå University, Skane University Hospital [Malmo], Lund University [Lund], RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche [Roma] (CNR), University Medical Center Groningen [Groningen] (UMCG), Universität Leipzig [Leipzig], Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Split, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), University of Eastern Finland, Harokopio University of Athens, European Academy Bozen/Bolzano (EURAC), University of Kuopio, German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Ninewells Hospital and Medical School [Dundee], University College of London [London] (UCL), University of Essex, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], University of Helsinki, Leiden University Medical Center (LUMC), Institute of Cardiovascular and Medical Sciences [Glasgow], University of Oulu, The University of Texas Health Science Center at Houston (UTHealth), University of Minnesota Medical School, University of Minnesota System, Keck School of Medicine [Los Angeles], University of Southern California (USC), Amsterdam UMC, University Hospital Carl Gustav Carus [Dresden, Germany], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Lee Kong Chian School of Medicine, Nanyang Technological University (NTU), Universität Heidelberg [Heidelberg], King Abdulaziz University, Pirkanmaa Hospital District, Tampere University Hospital, Cedars-Sinai Medical Center, Danube University Krems, Harvard School of Public Health, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institute of Epidemiology [Neuherberg] (EPI), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Hannover Medical School [Hannover] (MHH), Universität zu Lübeck [Lübeck], University of Exeter, Regeneron Pharmaceuticals [Tarrytown], University of Adelaide, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Harvard T.H. Chan School of Public Health, John Radcliffe Hospital [Oxford University Hospital], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Université de Genève (UNIGE), Big Data Institute, University of Surrey (UNIS), University of Bergen (UiB), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Stanford Cardiovascular Institute, University of Liverpool, University of Manchester [Manchester], Institute of Biochemistry and Genetics of Ufa Scientific Centre, Russian Academy of Sciences [Moscow] (RAS), Experimental Vascular Medicine, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, SIEST, Sofia, PreciDIAB Institute, the holistic approach of personal diabets care - - PreciDIAB2018 - ANR-18-IBHU-0001 - IBHU - VALID, Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging - DYNAHEALTH - - H20202015-04-01 - 2019-03-31 - 633595 - VALID, Beyond the Genetics of Addiction - ADDICTION - - EC:FP7:ERC2011-12-01 - 2017-05-31 - 284167 - VALID, Rise of scientific excellence and collaboration for implementing personalised medicine in Estonia - ePerMed - - H20202016-01-01 - 2018-12-31 - 692145 - VALID, University of Oxford, Helmholtz Zentrum München = German Research Center for Environmental Health, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Università degli Studi di Ferrara = University of Ferrara (UniFE), Université de Lausanne = University of Lausanne (UNIL), Karl-Franzens-Universität Graz, Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Amsterdam UMC - Amsterdam University Medical Center, Nanyang Technological University [Singapour], Universität zu Lübeck = University of Lübeck [Lübeck], Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, Université de Genève = University of Geneva (UNIGE), ANR-18-IBHU-0001,PreciDIAB,PreciDIAB Institute, the holistic approach of personal diabets care(2018), European Project: 633595,H2020,H2020-PHC-2014-two-stage,DYNAHEALTH(2015), European Project: 284167,EC:FP7:ERC,ERC-2011-StG_20101124,ADDICTION(2011), European Project: 692145,H2020,H2020-TWINN-2015,ePerMed(2016), Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Functional Genomics, APH - Mental Health, Sociology and Social Gerontology, APH - Methodology, Hottenga, Jouke- Jan [0000-0002-5668-2368], Bouatia-Naji, Nabila [0000-0001-5424-2134], Jansen, Rick [0000-0002-3333-6737], Min, Josine L. [0000-0003-4456-9824], Faggian, Alessia [0000-0002-3799-9722], Bonnefond, Amélie [0000-0001-9976-3005], Isaacs, Aaron [0000-0001-5037-4834], Willems, Sara M. [0000-0002-6803-3007], Navarro, Pau [0000-0001-5576-8584], Jackson, Anne U. [0000-0002-9672-2547], Bielak, Lawrence F. [0000-0002-3443-8030], Saxena, Richa [0000-0003-2233-1065], Smith, Albert V. [0000-0003-1942-5845], Verweij, Niek [0000-0002-4303-7685], Goel, Anuj [0000-0003-2307-4021], Johnson, Paul C. D. [0000-0001-6663-7520], Strawbridge, Rona J. [0000-0001-8506-3585], Fall, Tove [0000-0003-2071-5866], Fraser, Ross M. [0000-0003-0488-2592], Kanoni, Stavroula [0000-0002-1691-9615], Giedraitis, Vilmantas [0000-0003-3423-2021], Kleber, Marcus E. [0000-0003-0663-7275], Müller-Nurasyid, Martina [0000-0003-3793-5910], Luan, Jian’an [0000-0003-3137-6337], Sanna, Serena [0000-0002-3768-1749], Nolte, Ilja M. [0000-0001-5047-4077], Zemunik, Tatijana [0000-0001-8120-2891], Kovacs, Peter [0000-0002-0290-5423], Wild, Sarah H. [0000-0001-7824-2569], McLachlan, Stela [0000-0003-0480-6143], Egan, Josephine [0000-0002-8945-0053], Hicks, Andrew A. [0000-0001-6320-0411], Thorand, Barbara [0000-0002-8416-6440], Hingorani, Aroon [0000-0001-8365-0081], Kivimaki, Mika [0000-0002-4699-5627], Koistinen, Heikki A. [0000-0001-7870-070X], Bakker, Stephan J. L. [0000-0003-3356-6791], Palmer, Colin N. A. [0000-0002-6415-6560], Jukema, J. Wouter [0000-0002-3246-8359], Sattar, Naveed [0000-0002-1604-2593], Snieder, Harold [0000-0003-1949-2298], Magnusson, Patrik K. [0000-0002-7315-7899], Blüher, Matthias [0000-0003-0208-2065], Wolffenbuttel, Bruce H. R. [0000-0001-9262-6921], Abecasis, Goncalo R. [0000-0003-1509-1825], Meigs, James B. [0000-0002-2439-2657], Wilson, James F. [0000-0001-5751-9178], Schwarz, Peter E. H. [0000-0001-6317-7880], Boehm, Bernhard O. [0000-0002-2706-7710], Metspalu, Andres [0000-0002-3718-796X], Deloukas, Panos [0000-0001-9251-070X], Körner, Antje [0000-0001-6001-0356], Wareham, Nicholas J. [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], Männistö, Satu [0000-0002-8668-3046], Franks, Paul W. [0000-0002-0520-7604], Hayward, Caroline [0000-0002-9405-9550], Vitart, Veronique [0000-0002-4991-3797], Kaprio, Jaakko [0000-0002-3716-2455], Visvikis-Siest, Sophie [0000-0001-8104-8425], Altshuler, David [0000-0002-7250-4107], Rudan, Igor [0000-0001-6993-6884], van Duijn, Cornelia M. [0000-0002-2374-9204], Pramstaller, Peter P. [0000-0002-9831-8302], Boehnke, Michael [0000-0002-6442-7754], Frayling, Timothy M. [0000-0001-8362-2603], Peyser, Patricia A. [0000-0002-9717-8459], Harst, Pim van der [0000-0002-2713-686X], Smith, George Davey [0000-0002-1407-8314], Forouhi, Nita G. [0000-0002-5041-248X], Loos, Ruth J. F. [0000-0002-8532-5087], Salomaa, Veikko [0000-0001-7563-5324], Soranzo, Nicole [0000-0003-1095-3852], Boomsma, Dorret I. [0000-0002-7099-7972], Groop, Leif [0000-0002-0187-3263], Tuomi, Tiinamaija [0000-0002-8306-6202], Munroe, Patricia B. [0000-0002-4176-2947], Gudnason, Vilmundur [0000-0001-5696-0084], Lecoeur, Cecile [0000-0003-0075-6417], Jarvelin, Marjo-Riitta [0000-0002-2149-0630], Stefansson, Kari [0000-0003-1676-864X], Dermitzakis, Emmanouil T. [0000-0002-9302-6490], Lindgren, Cecilia M. [0000-0002-4903-9374], Froguel, Philippe [0000-0003-2972-0784], Kaakinen, Marika A. [0000-0002-9228-0462], Watanabe, Richard M. [0000-0003-1015-0531], Ingelsson, Erik [0000-0003-2256-6972], Dupuis, Josée [0000-0003-2871-3603], Barroso, Inês [0000-0001-5800-4520], Apollo - University of Cambridge Repository, Epidemiology, University Hospital Mannheim | Universitätsmedizin Mannheim, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Universität Leipzig, Universiteit Leiden, Universität Heidelberg [Heidelberg] = Heidelberg University, Karl-Franzens-Universität [Graz, Autriche], Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, General practice, APH - Digital Health, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Value, Affordability and Sustainability (VALUE), Cardiovascular Centre (CVC), Hottenga, Jouke-Jan [0000-0002-5668-2368], Min, Josine L [0000-0003-4456-9824], Willems, Sara M [0000-0002-6803-3007], Jackson, Anne U [0000-0002-9672-2547], Bielak, Lawrence F [0000-0002-3443-8030], Smith, Albert V [0000-0003-1942-5845], Johnson, Paul CD [0000-0001-6663-7520], Strawbridge, Rona J [0000-0001-8506-3585], Fraser, Ross M [0000-0003-0488-2592], Kleber, Marcus E [0000-0003-0663-7275], Luan, Jian'an [0000-0003-3137-6337], Nolte, Ilja M [0000-0001-5047-4077], Wild, Sarah H [0000-0001-7824-2569], Hicks, Andrew A [0000-0001-6320-0411], Koistinen, Heikki A [0000-0001-7870-070X], Bakker, Stephan JL [0000-0003-3356-6791], Palmer, Colin NA [0000-0002-6415-6560], Jukema, J Wouter [0000-0002-3246-8359], Magnusson, Patrik K [0000-0002-7315-7899], Wolffenbuttel, Bruce HR [0000-0001-9262-6921], Abecasis, Goncalo R [0000-0003-1509-1825], Meigs, James B [0000-0002-2439-2657], Wilson, James F [0000-0001-5751-9178], Schwarz, Peter EH [0000-0001-6317-7880], Boehm, Bernhard O [0000-0002-2706-7710], Wareham, Nicholas J [0000-0003-1422-2993], Franks, Paul W [0000-0002-0520-7604], van Duijn, Cornelia M [0000-0002-2374-9204], Pramstaller, Peter P [0000-0002-9831-8302], Frayling, Timothy M [0000-0001-8362-2603], Peyser, Patricia A [0000-0002-9717-8459], Forouhi, Nita G [0000-0002-5041-248X], Loos, Ruth JF [0000-0002-8532-5087], Boomsma, Dorret I [0000-0002-7099-7972], Munroe, Patricia B [0000-0002-4176-2947], Dermitzakis, Emmanouil T [0000-0002-9302-6490], Lindgren, Cecilia M [0000-0002-4903-9374], Kaakinen, Marika A [0000-0002-9228-0462], Watanabe, Richard M [0000-0003-1015-0531], Tampere University, Tays Research Services, Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC), Fysiologie, RS: FHML MaCSBio, and RS: Carim - B01 Blood proteins & engineering

Subjects
Male, Anorexia Nervosa, medicine.medical_treatment, 45/43, Insulin Resistance/genetics, SUSCEPTIBILITY, Quantitative trait, Impaired glucose tolerance, 0302 clinical medicine, Architecture, LS2_1, IMPUTATION, Insulin, ComputingMilieux_MISCELLANEOUS, Fasting, Publisher Correction, 3. Good health, [SDV] Life Sciences [q-bio], Kruppel-Like Transcription Factors/blood, Endokrinologi och diabetes, Science & Technology - Other Topics, Adult, Blood Glucose, European Continental Ancestry Group, Female, Gene Expression, Genetic Loci, Genome-Wide Association Study, Glucose Intolerance, Humans, Insulin Receptor Substrate Proteins, Insulin Resistance, Kruppel-Like Transcription Factors, Middle Aged, Phenotype, Sex Characteristics, Sex Factors, Waist-Hip Ratio, Sex characteristics, medicine.medical_specialty, Science, 631/208/205/2138, Endocrinology and Diabetes, General Biochemistry, Genetics and Molecular Biology, White People, Gender-differences, 03 medical and health sciences, SDG 3 - Good Health and Well-being, 692/53/2421, GLYCEMIC TRAITS, GENOME-WIDE ASSOCIATION, Glycemic, GENDER-DIFFERENCES, Science & Technology, IDENTIFICATION, 692/699/2743/2815, Blood Glucose/metabolism, Diagnostic markers, medicine.disease, Anorexia Nervosa/blood, 030104 developmental biology, Endocrinology, Glucose, Insulin/blood, Anorexia Nervosa/ethnology, Anorexia Nervosa/genetics, Anorexia Nervosa/physiopathology, Fasting/blood, Glucose Intolerance/blood, Glucose Intolerance/ethnology, Glucose Intolerance/genetics, Glucose Intolerance/physiopathology, Insulin Receptor Substrate Proteins/blood, Insulin Receptor Substrate Proteins/genetics, Kruppel-Like Transcription Factors/genetics, 0301 basic medicine, Identification, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Genome-wide association studies, Waist–hip ratio, LS4_5, RISK, ARCHITECTURE, Multidisciplinary, article, Type 2 diabetes, Multidisciplinary Sciences, MENDELIAN RANDOMIZATION, Pre-diabetes, Medical Genetics, Risk, PATHOPHYSIOLOGY, 030209 endocrinology & metabolism, 3121 Internal medicine, 692/163/2743/137/773, NO, Insulin resistance, Internal medicine, Diabetes mellitus, medicine, Mendelian randomization, 631/208/480, Medicinsk genetik, business.industry, General Chemistry, Impaired fasting glucose, business
Abstract

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes., Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.

Published
2021

4. Case–control analysis identifies shared properties of rare germline variation in cancer predisposing genes

Author

Kasmintan A. Schrader, Adam Kiezun, Tinu Thomas, Lauren Margolin, Namrata Gupta, Alexander J. Stratigos, Ivana K. Kim, Kristen M. Shannon, Gad Getz, Leif W. Ellisen, Steven M. Lipkin, Grace Tiao, Kenneth Offit, Robert J. Klein, Hensin Tsao, Vijai Joseph, Mykyta Artomov, Mark J. Daly, Daniel A. Haber, and David Altshuler

Subjects
Genetics, Candidate gene, Cancer-Predisposing Gene, Colorectal cancer, Cancer, Genome-wide association study, DNA, Biology, Brief Communication, medicine.disease, Germline, Cancer syndrome, Breast cancer, Case-Control Studies, Neoplasms, Inheritance Mode, medicine, Humans, Genetic Predisposition to Disease, Gene, Exome, Germ-Line Mutation, Genetics (clinical), Genetic association
Abstract

Along with traditional effects of aging and carcinogen exposure—inherited DNA variation has substantial contribution to cancer risk. Extraordinary progress made in analysis of common variation with GWAS methodology does not provide sufficient resolution to understand rare variation. To fulfill missing classification for rare germline variation we assembled dataset of whole exome sequences from>2000 patients (selected cases tested negative for candidate genes and unselected cases) with different types of cancers (breast cancer, colon cancer, and cutaneous and ocular melanomas) matched to more than 7000 non-cancer controls and analyzed germline variation in known cancer predisposing genes to identify common properties of disease-associated DNA variation and aid the future searches for new cancer susceptibility genes. Cancer predisposing genes were divided into non-overlapping classes according to the mode of inheritance of the related cancer syndrome or known tumor suppressor activity. Out of all classes only genes linked to dominant syndromes presented significant rare germline variants enrichment in cases. Separate analysis of protein-truncating and missense variation in this list of genes confirmed significant prevalence of protein-truncating variants in cases only in loss-of-function tolerant genes (pLI 0.9). In addition to findings in genetically enriched cases, we observed significant burden of rare variation in unselected cases, suggesting substantial role of inherited variation even in relatively late cancer manifestation. Taken together, our findings provide reference for distribution and types of DNA variation underlying inherited predisposition to some common cancer types.

Published
2019

5. Publisher Correction: Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author

Stavroula Kanoni, Bakker Sjl., Winkelmann Br, Wieland Kiess, Josée Dupuis, Palmer Cna., James F. Wilson, Schwarz Peh., Maria Dimitriou, Joop Jukema, Sara M. Willems, J L Min, R. Rauramaa, Perry Jrb., Momoko Horikoshi, Timo A. Lakka, Nicole Soranzo, J Kaprio, Niek Verweij, Martina Müller-Nurasyid, Jaana Lindström, Toby Johnson, Olga D. Carlson, Nita G. Forouhi, George Dedoussis, Johnson Pcd., Patrick K.E. Magnusson, Gonçalo R. Abecasis, Ozren Polasek, Wolffenbuttel Bhr., M. I. J. Uusitupa, Longda Jiang, Nancy L. Pedersen, Beate St Pourcain, Erik P A Van Iperen, Iva Miljkovic, Stefania Bandinelli, M. A. Province, Veikko Salomaa, Andrew A. Hicks, Evelin Mihailov, Rick Jansen, James B. Meigs, D Rybin, Peter Kovacs, George Davey Smith, Rona J. Strawbridge, Gudmar Thorleifsson, Meena Kumari, Chiara Scapoli, Christopher J. Groves, Barbara Thorand, T.B. Harris, Ulf de Faire, Inga Prokopenko, Stela McLachlan, Ping An, Anubha Mahajan, L.F. Bielak, Rebecca J. Webster, David Altshuler, Susan Campbell, Bernhard O. Boehm, A. Metspalu, Perttu Salo, D.I. Boomsma, Ilja M. Nolte, Andrea Ganna, Timothy M. Frayling, Pau Navarro, N J Timpson, Kardia Slr., Jeanette M. Stafford, Tõnu Esko, Ulrika Krus, Richa Saxena, Per Eriksson, Peter P. Pramstaller, Anne U. Jackson, V Lagou, Anders Franco-Cereceda, David S. Siscovick, Josephine M. Egan, Loos Rjf., C Gieger, Amanda J. Bennett, Anna Ulrich, Satu Männistö, Mika Kivimäki, Loic Yengo, Caroline Hayward, George Nicholson, C M van Duijn, Anke Tönjes, Nigel W. Rayner, Jose C. Florez, Leif Groop, Valeri Lyssenko, Lyle J. Palmer, Vilmantas Giedraitis, Maria G. Stathopoulou, B. Balkau, Anneli Pouta, Anuj Goel, Pierre Meneton, Serena Sanna, Jesper R. Gådin, Claudia Langenberg, Alessia Faggian, H Grallert, Karen Kapur, Marcus E. Kleber, Philippe Froguel, Boehnke M, Harry Campbell, Anders Hamsten, T. Saaristo, Antigone S. Dimas, Jarvelin M-R., F Karpe, A. Körner, Leena Kinnunen, Markus Perola, Joanne M. Meyer, May E. Montasser, Erik Ingelsson, Naveed Sattar, Yvonne Boettcher, Sirkka Keinänen-Kiukaanniemi, Aaron Isaacs, Gerjan Navis, Ian Ford, Amélie Bonnefond, Reedik Mägi, Tove Fall, Dmitry Shungin, Jenna Price, Igor Rudan, Richard M. Watanabe, Luigi Ferrucci, Jian'an Luan, Harst Pvd., Marika Kaakinen, Tatijana Zemunik, Christian Herder, Shin S-Y., Veronique Vitart, Ross M. Fraser, Alan R. Shuldiner, Panagiotis Deloukas, C. Lecoeur, Letizia Marullo, Kari Stefansson, Lars Lind, Winfried März, L Zudina, Aroon D. Hingorani, Gonneke Willemsen, de Geus Ejcn., Albert V. Smith, Jeffery R. O'Connell, Yongmei Liu, James S. Pankow, Sarah H. Wild, Patricia B. Munroe, Patricia A. Peyser, Nicholas J. Wareham, Tiinamaija Tuomi, Nicholas D. Hastie, Markku Laakso, Albert Hofman, J. Tuomilehto, Emmanouil T. Dermitzakis, Thomas Illig, Tomohiro Tanaka, Cecilia M. Lindgren, Sarin A-P., Alex S. F. Doney, Najaf Amin, Hugh Watkins, Johanna Kuusisto, Andrew P. Morris, Richard N. Bergman, Mark I. McCarthy, Nabila Bouatia-Naji, Günther Silbernagel, João Fadista, Harold Snieder, Ins Barroso, Michael Stumvoll, B.W.J.H. Penninx, M Blüher, Stefan R Bornstein, Laura J. Rasmussen-Torvik, Alan F. Wright, Peter Vollenweider, G K Hovingh, Heikki A. Koistinen, Sophie Visvikis-Siest, Vilmundur Gudnason, Eric Boerwinkle, Hottenga J-J., Guo Li, Paul W. Franks, Université de Lille, Centre de recherche en épidémiologie et santé des populations (CESP), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay

Subjects
Genetics, Multidisciplinary, Science, Insulin, medicine.medical_treatment, General Physics and Astronomy, Diagnostic marker, Genome-wide association study, General Chemistry, Type 2 diabetes, Quantitative trait locus, Biology, medicine.disease, GeneralLiterature_MISCELLANEOUS, General Biochemistry, Genetics and Molecular Biology, Fasting glucose, Sexual dimorphism, Pre diabetes, [SDU]Sciences of the Universe [physics], ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, medicine
Abstract

The original version of this Article contained an error in Fig. 2, in which panels a and b were inadvertently swapped. This has now been corrected in the PDF and HTML versions of the Article.

Published
2021

6. CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia

Author

Angela Yen, Damiano Rondelli, la Fuente Josu de, Amanda M. Li, Jennifer Domm, Montalembert Mariane de, Tony W. Ho, Donna A. Wall, Brenda K. Eustace, Juergen Foell, Sujit Sheth, Haydar Frangoul, Rupert Handgretinger, Akshay Sharma, Sandeep Soni, Antonis Kattamis, Andrew Kernytsky, Franco Locatelli, Stephan A. Grupp, M. Domenica Cappellini, Julie A. Lekstrom-Himes, Selim Corbacioglu, David Altshuler, Markus Y. Mapara, Yi-Shan Chen, and Martin H. Steinberg

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, Anemia, Thalassemia, Cell, CD34, Disease, Biology, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Genome editing, hemic and lymphatic diseases, Fetal hemoglobin, medicine, CRISPR, 030212 general & internal medicine, Progenitor cell, Enhancer, Genetics, business.industry, Obstetrics and Gynecology, General Medicine, medicine.disease, Haematopoiesis, medicine.anatomical_structure, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Immunology, Bone marrow, CRISPR-Cas9, business
Abstract

Transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD) are severe monogenic diseases with severe and potentially life-threatening manifestations. BCL11A is a transcription factor that represses γ-globin expression and fetal hemoglobin in erythroid cells. We performed electroporation of CD34+ hematopoietic stem and progenitor cells obtained from healthy donors, with CRISPR-Cas9 targeting the BCL11A erythroid-specific enhancer. Approximately 80% of the alleles at this locus were modified, with no evidence of off-target editing. After undergoing myeloablation, two patients - one with TDT and the other with SCD - received autologous CD34+ cells edited with CRISPR-Cas9 targeting the same BCL11A enhancer. More than a year later, both patients had high levels of allelic editing in bone marrow and blood, increases in fetal hemoglobin that were distributed pancellularly, transfusion independence, and (in the patient with SCD) elimination of vaso-occlusive episodes. (Funded by CRISPR Therapeutics and Vertex Pharmaceuticals; ClinicalTrials.gov numbers, NCT03655678 for CLIMB THAL-111 and NCT03745287 for CLIMB SCD-121.).

Published
2021

7. Functional characterization of tumor antigen-specific T-cells isolated from the tumor microenvironment of sleeping beauty induced murine glioma models

Author

Mahmoud S. Alghamri, Felipe J Nunez, Maria G. Castro, Neha Kamran, Pedro R. Lowenstein, David Altshuler, and Stephen Carney

Subjects
medicine.medical_treatment, Genetic enhancement, T cell, T-Lymphocytes, Thymidine Kinase, Article, Mice, Lymphocytes, Tumor-Infiltrating, Antigen, Antigens, Neoplasm, Glioma, medicine, Tumor Microenvironment, Animals, Tumor microenvironment, business.industry, Brain Neoplasms, Membrane Proteins, Immunotherapy, Genetic Therapy, medicine.disease, Cytotoxicity Tests, Immunologic, Primary tumor, Tumor antigen, medicine.anatomical_structure, Cancer research, business, Immunologic Memory
Abstract

Glioma is one of the most aggressive tumors. The median survival of the most aggressive form (Glioblastoma (GBM)) is approximately 14–20 months. The current standard of care includes tumor resection, chemotherapy and radiation, nevertheless, the incidence of recurrence remains high and there is a critical need for developing new therapeutic strategies. T-cell mediated immunotherapy that triggers an anti-tumor T cell-mediated memory response is a promising approach since it will not only attack the primary tumor but also prevent recurrence. Multiple immunotherapeutic strategies against glioma are currently being tested in clinical trials. We have developed an immune-mediated gene therapy (Thymidine kinase plus Fms-like tyrosine kinase 3 ligand: TK/Flt3L) which induces a robust anti-tumor T cell response leading to tumor regression, long-term survival and immunological memory in glioblastoma models. Efficacy of the anti-glioma T cell therapy is determined by anti-tumor specific effector T cells (Han et al., 2014). Therefore, assessing effector T cell activation status and function are critical readouts for assessing the effectiveness of the therapy. Here, we detail methodologies to evaluate tumor specific T-cell responses using a genetically engineered Sleeping Beauty transposase-mediated glioma model. We first describe the glioma model and the generation of neurospheres (NS) that express the surrogate antigen cOVA. Then, we describe functional assays to determine anti-tumor T-cell response.

Published
2020

8. Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes

Author

Teresa Tusié-Luna, Svati H. Shah, Wen-Jane Lee, Amit Khera, Gonçalo R. Abecasis, Olle Melander, Alan R. Shuldiner, Connor A. Emdin, Kari Stefansson, Jesper Gromada, Andrew P. Morris, Lee-Ming Chuang, Omri Gottesman, Lars G. Fritsche, Pradeep Natarajan, Marju Orho-Melander, Daniel F. Gudbjartsson, Anubha Mahajan, Marylyn D. Ritchie, William E. Kraus, Tooraj Mirshahi, Colm O'Dushlaine, Jason Flannick, Nicholas J. Wareham, Anne Tybjærg-Hansen, Anders Berg Wulff, Rashmi B. Prasad, Aris Baras, Jonas B. Nielsen, Valgerdur Steinthorsdottir, Yii-Der Ida Chen, Jerome I. Rotter, Lukas Habegger, Samantha N. Fetterolf, David Altshuler, Om Prakash Dwivedi, Tanya M. Teslovich, Cristen J. Willer, Luca A. Lotta, Andrew J. Murphy, Joseph B. Leader, Cristopher V. Van Hout, Christopher D. Still, Ola Hansson, David Birtwell, Alexander Lopez, Daniel J. Rader, John D. Overton, Anthony Marcketta, Patrick Sulem, Peter N. Benotti, Jose C. Florez, Lydia Coulter Kwee, David J. Carey, Oddgeir L. Holmen, Kristian Hveem, Leif Groop, Sekar Kathiresan, Viktoria Gusarova, Unnur Thorsteinsdottir, Cassandra M. Hartle, Uyenlinh L. Mirshahi, H. Lester Kirchner, Shannon Bruse, Robert A. Scott, Michael F. Murray, Marketa Sjögren, Jeffrey G. Reid, Aeron Small, Børge G. Nordestgaard, Amr H. Wardeh, Chad M. Brummett, Mark I. McCarthy, Frederick E. Dewey, David H. Ledbetter, John Penn, Ingrid B. Borecki, Scott M. Damrauer, Hilma Holm, Michael Boehnke, George D. Yancopoulos, Institute for Molecular Medicine Finland, University of Helsinki, Centre of Excellence in Complex Disease Genetics, and HUS Abdominal Center

Subjects
Blood Glucose, Male, 0301 basic medicine, Insulin Resistance/genetics, General Physics and Astronomy, Type 2 diabetes, 030204 cardiovascular system & hematology, Inbred C57BL, Cardiovascular, HAN CHINESE, Whole Exome Sequencing, Mice, 0302 clinical medicine, Risk Factors, ANGPTL4, Homeostasis, Glucose homeostasis, lcsh:Science, Mice, Knockout, Lipoprotein lipase, Multidisciplinary, Diabetes, Lipoprotein Lipase/metabolism, REMNANT CHOLESTEROL, ADIPOSE-TISSUE, Female, Type 2, Heterozygote, medicine.medical_specialty, Knockout, Science, LIPOPROTEIN-LIPASE, HEART-DISEASE, Diabetes Mellitus, Type 2/etiology, Article, General Biochemistry, Genetics and Molecular Biology, Angiopoietin-like 4 Protein/deficiency, 03 medical and health sciences, Internal medicine, Diabetes mellitus, Exome Sequencing, Diabetes Mellitus, Genetics, medicine, Angiopoietin-Like Protein 4, Animals, Humans, Gene Silencing, GENOME-WIDE ASSOCIATION, Metabolic and endocrine, Genetic Association Studies, CHINESE POPULATION, Blood Glucose/metabolism, PLASMA-LIPIDS, business.industry, Case-control study, Genetic Variation, General Chemistry, Odds ratio, Atherosclerosis, medicine.disease, Mice, Inbred C57BL, Lipoprotein Lipase, 030104 developmental biology, Endocrinology, Diabetes Mellitus, Type 2, Amino Acid Substitution, Case-Control Studies, lcsh:Q, 3111 Biomedicine, ANGIOPOIETIN-LIKE PROTEIN-4, Insulin Resistance, business
Abstract

Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85–0.92, p = 6.3 × 10−10), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49–0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D., Genetic variation in ANGPTL4 is associated with lipid traits. Here, the authors find that predicted loss-of-function variants in ANGPTL4 are associated with glucose homeostasis and reduced risk of type 2 diabetes and that Angptl4−/− mice on a high-fat diet show improved insulin sensitivity.

Published
2018

9. Molecular ablation of tumor blood vessels inhibits therapeutic effects of radiation and bevacizumab

Author

Andrea Comba, Maria G. Castro, Padma Kadiyala, Pedro R. Lowenstein, Carl Koschmann, Daniel Zamler, Patrick Dunn, Henry D. Appelman, David Altshuler, and Viveka Nand Yadav

Subjects
0301 basic medicine, Cancer Research, Bevacizumab, Endothelium, Angiogenesis, medicine.medical_treatment, Angiogenesis Inhibitors, Mice, Transgenic, Antiviral Agents, Thymidine Kinase, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Radiation, Ionizing, Glioma, Tumor Cells, Cultured, medicine, Animals, Humans, Simplexvirus, Ganciclovir, Chemotherapy, business.industry, Endothelial Cells, medicine.disease, Combined Modality Therapy, Survival Rate, Vascular endothelial growth factor, Endothelial stem cell, Vascular endothelial growth factor A, 030104 developmental biology, medicine.anatomical_structure, Oncology, chemistry, 030220 oncology & carcinogenesis, Basic and Translational Investigations, Cancer research, Neurology (clinical), business, medicine.drug
Abstract

Background Glioblastoma (GBM) is an aggressive and highly vascular tumor with median survival below 2 years. Despite advances in surgery, radiotherapy, and chemotherapy, survival has improved modestly. To combat glioma vascular proliferation, anti-angiogenic agents targeting vascular endothelial growth factor (VEGF) were introduced. Preclinically these agents were effective, yet they did not improve overall survival in phase III trials. We tested the hypothesis that ganciclovir (GCV)-mediated killing of proliferating endothelial cells expressing herpes simplex virus type 1 thymidine kinase (HSV1-TK) would have direct antitumor effects, and whether vessel ablation would affect the antitumor activity of anti-VEGF antibodies and radiotherapy. Methods Proliferating endothelial cells were eliminated using GCV-mediated killing of proliferating endothelial cells expressing HSV1-TK (in Tie2-TK-IRES-GFP mice). Syngeneic NRAS/p53 (NP) gliomas were implanted into the brains of Tie2-TK-IRES-GFP mice. Endothelial proliferation activates the Tie2 promoter and HSV1-TK expression. Administration of GCV kills proliferating tumor endothelial cells and slows tumor growth. The effects of endothelial cell ablation on anti-angiogenic therapy were examined using anti-VEGF antibodies or irradiation. Results GCV administration reduced tumor growth and vascular density, increased tumor apoptosis, and prolonged survival. Anti-VEGF antibodies or irradiation also prolonged survival. Surprisingly, combining GCV with irradiation, or with anti-VEGF antibodies, reduced their individual therapeutic effects. Conclusion GCV-mediated killing of proliferating endothelial cells expressing HSV1-TK, anti-VEGF antibodies, or irradiation all reduced growth of a murine glioma. However, elimination of microvascular proliferation decreased the efficacy of anti-VEGF or irradiation therapy. We conclude that, in our model, the integrity of proliferating vessels is necessary for the antiglioma effects of anti-VEGF and radiation therapy.

Published
2018

10. Ventriculoscopic Surgery for Cystic Retrochiasmatic Craniopharyngiomas: Indications, Surgical Technique, and Short-Term Patient Outcomes

Author

Ariel L. Barkan, Todd C. Hollon, David Altshuler, Stephen E. Sullivan, and Luis E. Savastano

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Radiography, Postoperative radiotherapy, 030209 endocrinology & metabolism, Preoperative care, Neurosurgical Procedures, Cerebral Ventricles, Craniopharyngioma, Young Adult, 03 medical and health sciences, 0302 clinical medicine, medicine, Foramen, Humans, Pituitary Neoplasms, Cyst, Aged, business.industry, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Tumor Burden, Surgery, Treatment Outcome, Hypothalamic dysfunction, Female, Neurology (clinical), Neoplasm Recurrence, Local, business, Fenestration, 030217 neurology & neurosurgery
Abstract

BACKGROUND Attempted gross-total resection for the management of cystic retrochiasmatic craniopharyngiomas can cause severe hypothalamic dysfunction and decrease overall survival. Ventriculoscopic surgery is a minimally invasive alternative; however, potential indications and technique have not been well defined. OBJECTIVE To present our indications and technique for the ventriculoscopic treatment of cystic retrochiasmatic craniopharyngiomas. METHODS We evaluated all patients with retrochiasmatic craniopharyngiomas for ventriculoscopic surgery. Indications and operative technique were developed to minimize operative morbidity, relieve mass effect, and optimize functional outcome. Cyst size and functional outcomes were statistically evaluated to determine radiographic and short-term clinical outcome. RESULTS Indications for ventriculoscopic surgery included (1) radiographic evidence of hypothalamic involvement and (2) major cystic component. Ten patients met indications, and mean follow-up was 2.5 ± 1.6 yr. The surgical technique included wide cyst fenestration at the foramen of Monro, and fenestration of inferior cyst wall/third ventriculostomy ("through-and-through" technique). Preoperative Karnofsky performance status was 70 ± 15 and was inversely correlated with preoperative cyst size (13 ± 13 cm3). A statistically significant reduction in cyst size was found on early postoperative imaging (2.1 ± 4.3 cm3). Seven patients received postoperative radiotherapy. Postoperative performance scores (81 ± 8.3) had improved; no patient suffered functional decline. Pre- and postoperative body mass indices were similar. No patient had short-term hypothalamic obesity. CONCLUSION Ventriculoscopic surgery, with or without adjuvant treatments, can reduce early postoperative tumor volume and improve short-term functional status in cystic retrochiasmatic craniopharyngiomas with hypothalamic involvement; it should be considered a minimally invasive option in the multimodal treatment of craniopharyngiomas. Further studies are needed to determine long-term efficacy.

Published
2017

11. Variation in Maturity-Onset Diabetes of the Young Genes Influence Response to Interventions for Diabetes Prevention

Author

Jarred B. McAteer, Dana Dabelea, Steven E. Kahn, Yu-Chien Cheng, Kathleen A. Jablonski, Toni I. Pollin, Alisa K. Manning, Liana K. Billings, Jose C. Florez, William C. Knowler, David A. Ehrmann, Laura Tipton, Paul W. Franks, Alan R. Shuldiner, David Altshuler, and A. Sofia Warner

Subjects
0301 basic medicine, medicine.medical_specialty, Diabetes, Pancreatic and Gastrointestinal Hormones, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Mutation, Missense, Context (language use), Placebo, Biochemistry, Polymorphism, Single Nucleotide, Maturity onset diabetes of the young, law.invention, 03 medical and health sciences, Endocrinology, Randomized controlled trial, law, Diabetes mellitus, Internal medicine, Glucokinase, medicine, Basic Helix-Loop-Helix Transcription Factors, Humans, Hepatocyte Nuclear Factor 1-alpha, Clinical Research Articles, Glycemic, Hepatocyte Nuclear Factor 1-beta, 2. Zero hunger, Homeodomain Proteins, business.industry, Biochemistry (medical), Genetic Variation, medicine.disease, Metformin, 3. Good health, Exercise Therapy, Minor allele frequency, Weight Reduction Programs, Editor's Choice, 030104 developmental biology, Treatment Outcome, Diabetes Mellitus, Type 2, Hepatocyte Nuclear Factor 4, Trans-Activators, business, Risk Reduction Behavior, medicine.drug
Abstract

Context: Variation in genes that cause maturity-onset diabetes of the young (MODY) has been associated with diabetes incidence and glycemic traits. Objectives: This study aimed to determine whether genetic variation in MODY genes leads to differential responses to insulin-sensitizing interventions. Design and Setting: This was a secondary analysis of a multicenter, randomized clinical trial, the Diabetes Prevention Program (DPP), involving 27 US academic institutions. We genotyped 22 missense and 221 common variants in the MODY-causing genes in the participants in the DPP. Participants and Interventions: The study included 2806 genotyped DPP participants randomized to receive intensive lifestyle intervention (n = 935), metformin (n = 927), or placebo (n = 944). Main Outcome Measures: Association of MODY genetic variants with diabetes incidence at a median of 3 years and measures of 1-year β-cell function, insulinogenic index, and oral disposition index. Analyses were stratified by treatment group for significant single-nucleotide polymorphism × treatment interaction (Pint < 0.05). Sequence kernel association tests examined the association between an aggregate of rare missense variants and insulinogenic traits. Results: After 1 year, the minor allele of rs3212185 (HNF4A) was associated with improved β-cell function in the metformin and lifestyle groups but not the placebo group; the minor allele of rs6719578 (NEUROD1) was associated with an increase in insulin secretion in the metformin group but not in the placebo and lifestyle groups. Conclusions: These results provide evidence that genetic variation among MODY genes may influence response to insulin-sensitizing interventions., Genetic variation in MODY genes was associated with response to diabetes prevention interventions as measured by β-cell function and diabetes incidence.

Published
2017

12. ATIM-44. A PHASE I FIRST-IN-HUMAN TRIAL OF TWO ADENOVIRAL VECTORS EXPRESSING HSV1-TK AND FLT3L FOR TREATING NEWLY DIAGNOSED RESECTABLE MALIGNANT GLIOMA: THERAPEUTIC REPROGRAMMING OF THE BRAIN IMMUNE SYSTEM

Author

Jason Heth, Sriram Venneti, Theodore S. Lawrence, Daniel R. Wahl, Paul E. McKeever, Yoshie Umemura, Karin M. Muraszko, Michelle M. Kim, Sandra Camelo-Piragua, Pedro R. Lowenstein, Aaron Mammoser, Shawn L. Hervey-Jumper, Maria G. Castro, Oren Sagher, Andrew P. Lieberman, Daniel A. Orringer, Denise Leung, Andrea Comba, David Altshuler, and Larry Junck

Subjects
Cancer Research, business.industry, Adult Clinical Trials–Immunologic, Newly diagnosed, First in human, medicine.disease, Immune system, Oncology, Glioma, Cancer research, Medicine, Neurology (clinical), business, Reprogramming
Abstract

This is an interim report on a first in human Phase I dose escalation trial of the combination of two adenoviral vectors expressing HSV1-TK or Flt3L for the treatment of newly diagnosed, resectable malignant gliomas. Lack of dendritic cells from the brain precludes anti-glioma immune responses. We combined tumor cytotoxicity (Ad-HSV1TK) with recruitment of dendritic cells to gliomas (Ad-Flt3L) to induce anti-glioma immunity. In experimental models this treatment induces powerful cytotoxic CD8 and CD4 T-dependent anti-glioma immunity, immunological memory, and the capacity to recognize neo-antigens. The trial was approved through a FDA-IND, and all institutional cttees. Treatment was administered intraoperatively following complete glioma resection in newly diagnosed tumors. The trial consisted of vector dose escalation, starting at 1x10^9 v.p., and increasing to 1x10^11 v.p. of each vector, through 6 cohorts of 3 patients each. Two cycles of 14 days of valacyclovir were administered to activate HSV1-TK cytotoxicity. Cycle 1 starts on Day 1–3 post surgery for 14 days, and Cycle 2 on Week 8–12. Standard radiation, i.e., 60 Gy in 2 Gy fractions over 6 weeks, with concurrent temozolomide, was followed by cyclic temozolomide. Examination of tumor samples at primary resection and first recurrence show an increase in the infiltration of inflammatory cells. The experimental treatment was well tolerated. An MTD was not reached. There were approx. 248 AEs, and 26 SAEs; these were not linked to treatment. As secondary outcome, median survival of contemporary controls was 604 days, and median survival of trial patients was 742 days. Our results show for the first time that reprogramming of the host’s brain immune system to recognize gliomas reveals a new approach for the treatment of highly malignant brain tumors. Clinical trial information: NCT01811992.

Published
2019

13. LGG-17. DECREASED FUNCTION OF ISOPRENYLCYSTEINE CARBOXYLMETHYLTRANSFERASE RESULTS IN INCREASED SENSITIVITY TO CHEMORADIATION IN OLIGODENDROGLIOMA

Author

Pedro R. Lowenstein, Viveka Nand Yadav, Maria Ventosa Rosales, Maria G. Castro, and David Altshuler

Subjects
Medulloblastoma, Cancer Research, Carmustine, Vincristine, business.industry, Low Grade Glioma, medicine.disease, Procarbazine, Chemotherapy regimen, Oncology, Glioma, Cancer research, medicine, Isoprenylcysteine carboxylmethyltransferase, Neurology (clinical), Oligodendroglioma, business, medicine.drug
Abstract

Oligodendroglioma is an indolent, chemosensitive glioma characterized by 1p/19q co-deletion. This loss of genetic information may be responsible for its unique treatment sensitivity. Our preliminary data suggests a role for the 1p gene, isoprenylcysteine carboxylmethyltransferase (ICMT). ICMT is the only enzyme to methylate prenylcysteine subtrates and has broad influence on lamin A function in the nucleus. We hypothesized that ICMT may be responsible for the unique treatment sensitivity of oligodendroglioma. An in vivo brain tumor model was established in ICMT knock-down transgenic mice whereby subventricular zone cells of neonates were transfected with oncogenic plasmids and a transposase to generate a tumor, recapitulating de novo glial oncogenesis. A Kaplan-Meier analysis was performed for mice treated with CCNU chemotherapy grouped according to ICMT expression levels from low to high by genotype (hypomorphic, heteromorphic, or wildtype). In vitro RNA interference studies were performed in glioma cell lines expressing a short-hairpin against ICMT. Procarbazine, carmustine, vincristine (PCV) and radiosensitivity assays were performed. The impact of ICMT inhibition on lamin A function was characterized by immunofluorescence. There was a significant difference in the median overall survival of CCNU treated transgenic mice by ICMT genotype. Hypomorphic mice had the longest median survival (91±29 days,n=9) compared to heteromorphs (78±19,n=14) and wildtype (72±44,n=16). In vitro, cells with ICMT inhibited demonstrated increased sensitivity to PCV and radiation. Lamin A immunofluorescence revealed disrupted nuclear membranes in ICMT-inhibited cells, suggesting potential increased sensitivity to DNA damaging agents. The 1p/19q co-deletion that is a characteristic of oligodendroglioma may be related to its unique treatment sensitivity. Preliminary in vivo and in vitro data implicate ICMT as a gene on chromosome 1p that may play an important role. Further characterization of the involved molecular mechanisms may lead to novel therapeutic strategies that exploit associated vulnerabilities in oligodendroglioma and other glial neoplasms. MEDULLOBLASTOMA

Published
2019

14. High-Density Lipoprotein-Mimicking Nanodiscs for Chemo-immunotherapy against Glioblastoma Multiforme

Author

Maria G. Castro, Padma Kadiyala, Robert Doherty, Minzhi Yu, Neha Kamran, David Altshuler, Dan Li, Rui Kuai, Pedro R. Lowenstein, James J. Moon, Marta Edwards, Fernando M. Nunez, and Anna Schwendeman

Subjects
Paclitaxel, T-Lymphocytes, T cell, Brain tumor, General Physics and Astronomy, Docetaxel, 02 engineering and technology, 010402 general chemistry, Models, Biological, 01 natural sciences, Article, Mice, Drug Delivery Systems, Lomustine, Cell Line, Tumor, Glioma, medicine, Animals, Humans, General Materials Science, Cell Proliferation, Tumor microenvironment, business.industry, General Engineering, TLR9, Flow Cytometry, 021001 nanoscience & nanotechnology, medicine.disease, Immunohistochemistry, Rats, 0104 chemical sciences, medicine.anatomical_structure, Drug delivery, Cancer research, Female, Immunotherapy, Glioblastoma, Lipoproteins, HDL, 0210 nano-technology, business, CD8, medicine.drug
Abstract

Glioblastoma multiforme (GBM) is an aggressive primary brain tumor, for which there is no cure. Treatment effectiveness for GBM has been limited due to tumor heterogeneity, an immunosuppressive tumor microenvironment (TME) and the presence of the blood brain barrier, which hampers the transport of chemotherapeutic compounds to the central nervous system (CNS). High-density lipoprotein (HDL)-mimicking nanodiscs hold considerable promise to achieve delivery of bioactive compounds into tumors. Herein, we tested the ability of synthetic HDL nanodiscs, to deliver chemotherapeutic agents to the GBM microenvironment and elicit tumor regression. To this end, we developed chemo-immunotherapy delivery vehicles based on sHDL nanodiscs loaded with CpG, a Toll-like receptor 9 (TLR9) agonist, together with docetaxel (DTX), a chemotherapeutic agent, for targeting GBM. Our data show that delivery of DTX-sHDL-CpG nanodiscs into the tumor mass elicited tumor regression and anti-tumor CD8(+) T cell responses in the brain TME. We did not observe any overt off-target side effects. Furthermore, the combination of DTX-sHDL-CpG treatment with radiation (IR), which is the standard of care for GBM, resulted in tumor regression and long-term survival in 80% of GBM-bearing animals. Mice remained tumor free upon tumor cell rechallenge in the contralateral hemisphere, indicating the development of anti-GBM immunological memory. Collectively, these data indicate that sHDL nanodiscs constitute an effective drug delivery platform for the treatment of GBM, resulting in tumor regression, long term survival and immunological memory, when used in combination with IR. The proposed delivery platform has significant potential for clinical translation.

Published
2019

15. Circulating sex hormone binding globulin levels are modified with intensive lifestyle intervention, but their changes did not independently predict diabetes risk in the Diabetes Prevention Program

Author

Mike Reidy, Christine Lee, Michael Brändle, Sherita Hill Golden, Samuel Dagogo-Jack, David Kessler, Elizabeth Barrett-Connor, Steve Jones, Ling Chen, Judith Wylie-Rosett, Ping Zhang, Paula Williamson, Carlos Lorenzo, Leigh Perreault, Dana Dabelea, Santica Marcovina, Rachel Williams, Marie Smith, Carmen Pal, Patricia Katz, William H. Herman, Sharon L Edelstein, Yong Ma, Vanita R Aroda, Costas A Christophi, Catherine Kim, Sherita H Golden, Edward Horton, Kieren J Mather, George A. Bray, Kishore Gadde, Iris W. Culbert, Jennifer Arceneaux, Annie Chatellier, Amber Dragg, Catherine M. Champagne, Crystal Duncan, Barbara Eberhardt, Frank Greenway, Fonda G. Guillory, April A. Herbert, Michael L. Jeffirs, Betty M. Kennedy, Erma Levy, Monica Lockett, Jennifer C. Lovejoy, Laura H. Morris, Lee E. Melancon, Donna H. Ryan, Deborah A. Sanford, Kenneth G. Smith, Lisa L. Smith, Julia A. St, Richard T. Tulley Amant, Paula C. Vicknair, Donald Williamson, Jeffery J. Zachwieja, Kenneth S. Polonsky, Janet Tobian, David A. Ehrmann, Margaret J. Matulik, Bart Clark, Kirsten Czech, Catherine DeSandre, Ruthanne Hilbrich, Wylie McNabb, Ann R. Semenske, Jose F. Caro, Kevin Furlong, Barry J. Goldstein, Pamela G. Watson, Kellie A. Smith, Jewel Mendoza, Wendi Wildman, Renee Liberoni, John Spandorfer, Constance Pepe, Richard P. Donahue, Ronald B. Goldberg, Ronald Prineas, Jeanette Calles, Juliet Ojito, Patricia Rowe, Paul Cassanova-Romero, Sumaya Castillo-Florez, Hermes J. Florez, Anna Giannella, Lascelles Kirby, Carmen Larreal, Olga Lara, Valerie McLymont, Jadell Mendez, Arlette Perry, Patrice Saab, Beth Veciana, Steven M. Haffner, Helen P. Hazuda, Maria G. Montez, Kathy Hattaway, Arlene Martinez, Tatiana Walker, Richard F. Hamman, Patricia V. Nash, Sheila C. Steinke, Lisa Testaverde, Denise R. Anderson, Larry B. Ballonoff, Alexis Bouffard, Brian Bucca, B. Ned Calonge, Lynne Delve, Martha Farago, James O. Hill, Shelley R. Hoyer, Tonya Jenkins, Bonnie T. Jortberg, Dione Lenz, Marsha Miller, David W. Price, Judith G. Regensteiner, Helen Seagle, Carissa M. Smith, Brent VanDorsten, Edward S. Horton, Kathleen E. Lawton, Catherine S. Poirier, Kati Swift, Ronald A. Arky, Marybeth Bryant, Jacqueline P. Burke, Enrique Caballero, Karen M. Callaphan, Barbara Fargnoli, Therese Franklin, Om P. Ganda, Ashley Guidi, Mathew Guido, Sharon D. Jackson, Alan M. Jacobsen, Lori Lambert, Sarah Ledbury, Margaret Kocal, Lyn M. Kula, Maureen A. Malloy, Maryanne Nicosia, Cathryn F. Oldmixon, Jocelyn Pan, Marizel Quitingon, Stacy Rubtchinsky, Jessica Sansoucy, Dana Schweizer, Ellen W. Seely, Donald Simonson, Fannie Smith, Caren G. Solomon, Jeanne Spellman, James Warram, Steven E. Kahn, Brenda K. Montgomery, Wilfred Fujimoto, Robert H. Knopp, Edward W. Lipkin, Michelle Marr, Ivy Morgan-Taggart, Anne Murillo, Dace Trence, Lonnese Taylor, April Thomas, Elaine C. Tsai, Abbas E. Kitabchi, Mary E. Murphy, Laura Taylor, Jennifer Dolgoff, William B. Applegate, Michael Bryer-Ash, Debra Clark, Sandra L. Frieson, Uzoma Ibebuogu, Raed Imseis, Helen Lambeth, Lynne C. Lichtermann, Hooman Oktaei, Harriet Ricks, Lily M.K. Rutledge, Amy R. Sherman, Clara M. Smith, Judith E. Soberman, Beverly Williams-Cleaves, Boyd E. Metzger, Mark E. Molitch, Mariana K. Johnson, Daphne T. Adelman, Catherine Behrends, Michelle Cook, Marian Fitzgibbon, Mimi M. Giles, Deloris Heard, Cheryl K.H. Johnson, Diane Larsen, Anne Lowe, Megan Lyman, David McPherson, Samsam C. Penn, Thomas Pitts, Renee Reinhart, Susan Roston, Pamela A. Schinleber, David M. Nathan, Charles McKitrick, Heather Turgeon, Mary Larkin, Kathy Abbott, Ellen Anderson, Laurie Bissett, Kristy Bondi, Enrico Cagliero, Jose C. Florez, Kali D’Anna, Linda Delahanty, Valerie Goldman, Peter Lou, Alexandra Poulos, Elyse Raymond, Christine Stevens, Beverly Tseng, Jerrold M. Olefsky, Mary Lou Carrion-Petersen, Madeline Beltran, Lauren N. Claravall, Jonalle M. Dowden, Steven V. Edelman, Robert R. Henry, Javiva Horne, Marycie Lamkin, Simona Szerdi Janesch, Diana Leos, Sunder Mudaliar, William Polonsky, Jean Smith, Jennifer Torio-Hurley, Karen Vejvoda, F. Xavier Pi-Sunyer, Jane E. Lee, David B. Allison, Nnenna Agharanya, Nancy J. Aronoff, Maria Baldo, Jill P. Crandall, Sandra T. Foo, Susan Hagamen, Jose A. Luchsinger, Kathy Parkes, Mary Beth Pena, Ellen S. Rooney, Gretchen E.H. Van Wye, Kristine A. Viscovich, David G. Marrero, Kieren J. Mather, Melvin J. Prince, Susie M. Kelly, Marcia A. Jackson, Gina McAtee, Paula Putenney, Ronald T. Ackermann, Carolyn M. Cantrell, Yolanda F. Dotson, Edwin S. Fineberg, Megan Fultz, John C. Guare, Angela Hadden, James M. Ignaut, Marion S. Kirkman, Erin O’Kelly Phillips, Beverly D. Porter, Paris J. Roach, Nancy D. Rowland, Madelyn L. Wheeler, Vanita Aroda, Robert E. Ratner, Gretchen Youssef, Sue Shapiro, Catherine Bavido-Arrage, Geraldine Boggs, Marjorie Bronsord, Ernestine Brown, Wayman W. Cheatham, Susan Cola, Cindy Evans, Peggy Gibbs, Tracy Kellum, Renee Wiggins, Milvia Lagarda, Lilia Leon, Claresa Levatan, Milajurine Lindsay, Asha K. Nair, Maureen Passaro, Angela Silverman, Gabriel Uwaifo, Debra Wells-Thayer, Mohammed F. Saad, Karol Watson, Maria Budget, Sujata Jinagouda, Medhat Botrous, Khan Akbar, Claudia Conzues, Perpetua Magpuri, Kathy Ngo, Amer Rassam, Debra Waters, Kathy Xapthalamous, Julio V. Santiago, Neil H. White, Angela L. Brown, Samia Das, Prajakta Khare-Ranade, Tamara Stich, Ana Santiago, Edwin Fisher, Emma Hurt, Tracy Jones, Michelle Kerr, Lucy Ryder, Cormarie Wernimont, Christopher D. Saudek, Vanessa Bradley, Emily Sullivan, Tracy Whittington, Caroline Abbas, Adrienne Allen, Frederick L. Brancati, Sharon Cappelli, Jeanne M. Clark, Jeanne B. Charleston, Janice Freel, Katherine Horak, Alicia Greene, Dawn Jiggetts, Deloris Johnson, Hope Joseph, Kimberly Loman, Henry Mosley, John Reusing, Richard R. Rubin, Alafia Samuels, Thomas Shields, Shawne Stephens, Kerry J. Stewart, LeeLana Thomas, Evonne Utsey, David S. Schade, Karwyn S. Adams, Janene L. Canady, Carolyn Johannes, Claire Hemphill, Penny Hyde, Leslie F. Atler, Patrick J. Boyle, Mark R. Burge, Lisa Chai, Kathleen Colleran, Ysela Gonzales, Doris A. Hernandez-McGinnis, Carolyn King, Sofya Rubinchik, Willette Senter, Jill Crandall, Harry Shamoon, Janet O. Brown, Gilda Trandafirescu, Elsie Adorno, Liane Cox, Helena Duffy, Samuel Engel, Allison Friedler, Angela Goldstein, Crystal J. Howard-Century, Jennifer Lukin, Stacey Kloiber, Nadege Longchamp, Helen Martinez, Dorothy Pompi, Jonathan Scheindlin, Elissa Violino, Elizabeth A. Walker, Elise Zimmerman, Joel Zonszein, Trevor Orchard, Rena R. Wing, Susan Jeffries, Gaye Koenning, M. Kaye Kramer, Susan Barr, Catherine Benchoff, Miriam Boraz, Lisa Clifford, Rebecca Culyba, Marlene Frazier, Ryan Gilligan, Stephanie Guimond, Susan Harrier, Louann Harris, Andrea Kriska, Bonny Rockette-Wagner, Qurashia Manjoo, Monica Mullen, Alicia Noel, Amy Otto, Jessica Pettigrew, Debra Rubinstein, Linda Semler, Cheryl F. Smith, Elizabeth Venditti, Valarie Weinzierl, Katherine V. Williams, Tara Wilson, Richard F. Arakaki, Renee W. Latimer, Narleen K. Baker-Ladao, Mae K. Isonaga, Ralph Beddow, Nina E. Bermudez, Lorna Dias, Jillian Inouye, Marjorie K. Mau, John S. Melish, Kathy Mikami, Pharis Mohideen, Sharon K. Odom, Raynette U. Perry, Robin E. Yamamoto, William C. Knowler, Norman Cooeyate, Mary A. Hoskin, Carol A. Percy, Alvera Enote, Camille Natewa, Kelly J. Acton, Vickie L. Andre, Rosalyn Barber, Shandiin Begay, Peter H. Bennett, Mary Beth Benson, Evelyn C. Bird, Brenda A. Broussard, Brian C. Bucca, Marcella Chavez, Sherron Cook, Jeff Curtis, Tara Dacawyma, Matthew S. Doughty, Roberta Duncan, Charlotte Dodge, Cyndy Edgerton, Jacqueline M. Ghahate, Justin Glass, Martia Glass, Dorothy Gohdes, Wendy Grant, Robert L. Hanson, Ellie Horse, Louise E. Ingraham, Merry Jackson, Priscilla Jay, Roylen S. Kaskalla, Kathleen M. Kobus, Jonathan Krakoff, Jason Kurland, Catherine Manus, Cherie McCabe, Sara Michaels, Tina Morgan, Yolanda Nashboo, Julie A. Nelson, Steven Poirier, Evette Polczynski, Christopher Piromalli, Jeanine Roumain, Debra Rowse, Robert J. Roy, Sandra Sangster, Janet Sewenemewa, Miranda Smart, Darryl Tonemah, Charlton Wilson, Michelle Yazzie, Raymond Bain, Sarah Fowler, Marinella Temprosa, Michael D. Larsen, Tina Brenneman, Sharon L. Edelstein, Solome Abebe, Julie Bamdad, Melanie Barkalow, Joel Bethepu, Tsedenia Bezabeh, Nicole Butler, Jackie Callaghan, Caitlin E. Carter, Costas Christophi, Gregory M. Dwyer, Mary Foulkes, Yuping Gao, Robert Gooding, Adrienne Gottlieb, Kristina L. Grimes, Nisha Grover-Fairchild, Lori Haffner, Heather Hoffman, Kathleen Jablonski, Tara L. Jones, Richard Katz, Preethy Kolinjivadi, John M. Lachin, Pamela Mucik, Robert Orlosky, Qing Pan, Susan Reamer, James Rochon, Alla Sapozhnikova, Hanna Sherif, Charlotte Stimpson, Ashley Hogan Tjaden, Fredricka Walker-Murray, Elizabeth M. Venditti, Andrea M. Kriska, Valerie Weinzierl, Jessica Harting, F. Alan Aldrich, John Albers, Greg Strylewicz, R. Eastman, Judith Fradkin, Sanford Garfield, Edward Gregg, Morton B. Brown, David Altshuler, Liana K. Billings, Maegan Harden, Toni I. Pollin, Alan R. Shuldiner, Paul W. Franks, and Marie-France Hivert

Subjects
Male, Aging, Endocrinology, Diabetes and Metabolism, primary prevention, Overweight, Cardiovascular, Medical and Health Sciences, lcsh:Diseases of the endocrine glands. Clinical endocrinology, law.invention, Impaired glucose tolerance, 0302 clinical medicine, Sex hormone-binding globulin, Randomized controlled trial, law, Sex Hormone-Binding Globulin, polycyclic compounds, skin and connective tissue diseases, reproductive and urinary physiology, biology, DPP Research Group, Diabetes, Metformin, type 2, 030220 oncology & carcinogenesis, diabetes mellitus, Female, Clinical care/Education/Nutrition, medicine.symptom, hormones, hormone substitutes, and hormone antagonists, medicine.drug, medicine.medical_specialty, Diabetes risk, hormone, Clinical Trials and Supportive Activities, Clinical Sciences, 030209 endocrinology & metabolism, Placebo, 03 medical and health sciences, Clinical Research, Internal medicine, Diabetes mellitus, Health Sciences, Glucose Intolerance, Diabetes Mellitus, medicine, Humans, Obesity, Life Style, Metabolic and endocrine, Nutrition, lcsh:RC648-665, business.industry, Prevention, life style, medicine.disease, Estrogen, Diabetes Mellitus, Type 2, biology.protein, 3.1 Primary prevention interventions to modify behaviours or promote wellbeing, sense organs, business
Abstract

IntroductionSex hormone binding globulin (SHBG) levels are reported to be inversely associated with diabetes risk. It is unknown whether diabetes prevention interventions increase SHBG and whether resultant changes in SHBG affect diabetes risk. The purpose of this analysis was to determine whether intensive lifestyle intervention (ILS) or metformin changed circulating SHBG and if resultant changes influenced diabetes risk in the Diabetes Prevention Program (DPP).Research design and methodsThis is a secondary analysis from the DPP (1996–2001), a randomized trial of ILS or metformin versus placebo on diabetes risk over a mean follow-up of 3.2 years. The DPP was conducted across 27 academic study centers in the USA. Men, premenopausal and postmenopausal women without hormone use in the DPP were evaluated. The DPP included overweight/obese persons with elevated fasting glucose and impaired glucose tolerance. Main outcomes measures were changes in SHBG levels at 1 year and risk of diabetes over 3 years.ResultsILS resulted in significantly higher increases (postmenopausal women: pConclusionsLifestyle intervention may be associated with favorable changes in circulating SHBG, which is largely due to changes in adiposity. Changes in circulating SHBG do not independently predict reductions in diabetes incidence.

Published
2020

16. Functional Investigations of HNF1A Identify Rare Variants as Risk Factors for Type 2 Diabetes in the General Population

Author

Noël P. Burtt, Jason Flannick, Anders Molven, Janne Molnes, Laeya A. Najmi, Ingvild Aukrust, David Altshuler, Pål R. Njølstad, Leif Groop, Lise Bjørkhaug, and Stefan Johansson

Subjects
Male, Transcriptional Activation, 0301 basic medicine, Diabetes risk, Genotype, Endocrinology, Diabetes and Metabolism, Population, MODY 3, 030209 endocrinology & metabolism, Type 2 diabetes, Biology, Bioinformatics, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Odds Ratio, Internal Medicine, medicine, Humans, Genetic Predisposition to Disease, Hepatocyte Nuclear Factor 1-alpha, education, Allele frequency, Genetics, education.field_of_study, Genetic Variation, Odds ratio, medicine.disease, HNF1A, Minor allele frequency, Metabolism, 030104 developmental biology, Diabetes Mellitus, Type 2, Female, HeLa Cells
Abstract

Variants in HNF1A encoding hepatocyte nuclear factor 1α (HNF-1A) are associated with maturity-onset diabetes of the young form 3 (MODY 3) and type 2 diabetes. We investigated whether functional classification of HNF1A rare coding variants can inform models of diabetes risk prediction in the general population by analyzing the effect of 27 HNF1A variants identified in well-phenotyped populations (n = 4,115). Bioinformatics tools classified 11 variants as likely pathogenic and showed no association with diabetes risk (combined minor allele frequency [MAF] 0.22%; odds ratio [OR] 2.02; 95% CI 0.73–5.60; P = 0.18). However, a different set of 11 variants that reduced HNF-1A transcriptional activity to

Published
2016

17. Abstract CT105: First in human phase I trial of adenoviral vectors expressing Flt3L and HSV1-TK to treat newly diagnosed high-grade glioma by reprogramming the brain immune system

Author

Larry Junck, Mishell Kim, Karen Sagher, Yoshie Umemura, Paul E. McKeever, Daniel Zamler, David Altshuler, Daniel A. Orringer, Sriram Venneti, Lili Zhao, Pedro R. Lowenstein, Oren Sagher, Jason Heth, Andrew P. Lieberman, Daniel Wahl, Sandra Camelo-Piragua, Patrick Dunn, Aaron Mammoser, Shawn L. Hervey-Jumper, Andrea Comba, Theodore Lawrence, Kait Verbal, Maria G. Castro, Denise Leung, and Karin M. Muraszko

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Temozolomide, business.industry, medicine.medical_treatment, T cell, medicine.disease, Immune system, medicine.anatomical_structure, Antigen, Internal medicine, Glioma, medicine, Clinical endpoint, business, Adjuvant, CD8, medicine.drug
Abstract

High grade gliomas (HGG) such as glioblastoma lack effective treatment with poor prognosis of median overall survival (OS) around 14-16 months with standard of care. Initiation of effective immune response against cancer requires functional dendritic cells, which are absent from the central nervous system, resulting in lack of anti-HGG immune responses. An effective anti-glioma immune response can be achieved by combining glioma cytotoxicity with HSV1-TK and valacyclovir, and recruitment of dendritic cells to the brain with Flt3L. This dual approach makes endogenous tumor antigens available to infiltrating dendritic cells in its microenvironment by causing: (i) dendritic cells' infiltration of gliomas, (ii) CD8+, CD4+ T cell immune cytotoxicity and memory, and (iii) the systemic immune system to recognize tumor neoantigens. We report the first in human phase I dose escalation trial of adenoviral vectors expressing HSV1-TK and Flt3L (NCT01811992). Injection of dose escalated HSV1-TK and Flt3L adenovectors (range 1x10^9 vp - 1x10^11 vp) to the tumor bed post-resection of newly diagnosed HGG was followed by two cycles of 14-day course of valacyclovir starting 1-3 days and 10-12 weeks post-op combined with standard of care upfront radiation, concurrent and adjuvant temozolomide. Key inclusion criteria were ages 18-75, KPS ≥70, and suspected newly diagnosed HGG amenable to gross total resection. Enrollment and vector injection occurred after frozen pathology confirmed HGG. Out of 18 patients, six are still alive. The primary endpoint of maximal tolerated dose was not reached and the experimental treatment was well tolerated without dose limiting toxicity. The secondary endpoint of OS is promising with median of 21.9 months (range 5.4-52.7). Five out of six patients (83%) who had re-resection at the time of suspected radiographic progression had treatment effect rather than true progression, and increase in markers for dendritic cells, CD4+ T cells, and macrophages were noted, indicating successful immunity recruitment consistent with pre-clinical findings. Updated survival data, as well as comparison to matched controls, and detailed toxicities will be presented at the time of the meeting. In conclusion, the use of dual adenoviral vectors expressing Flt3L and HSV1-TK is safe and well tolerated in newly diagnosed HGG patients. Our results indicate promising preliminary survival outcome and histological evidence of immune infiltration. Future studies to assess treatment efficacy is warranted. Citation Format: Pedro Lowenstein, Daniel Orringer, Yoshie Umemura, Oren Sagher, Jason Heth, Shawn Hervey-Jumper, Aaron Mammoser, Denise Leung, Ted Lawrence, Mishell Kim, Daniel Wahl, Paul McKeever, Sandra Camelo-Piragua, Andrew Lieberman, Sriram Venneti, Kait Verbal, Karen Sagher, Patrick Dunn, Daniel Zamler, Andrea Comba, David Altshuler, Lili Zhao, Karin Muraszko, Larry Junck, Maria G. Castro. First in human phase I trial of adenoviral vectors expressing Flt3L and HSV1-TK to treat newly diagnosed high-grade glioma by reprogramming the brain immune system [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT105.

Published
2020

18. Mutant ATRX: uncovering a new therapeutic target for glioma

Author

Maria B. Garcia-Fabiani, Fernando M. Nunez, Santiago Haase, Stephen Carney, Maria G. Castro, David Altshuler, Flor M. Mendez, Pedro R. Lowenstein, and Felipe J Nunez

Subjects
0301 basic medicine, Adult, X-linked Nuclear Protein, DNA damage, Clinical Biochemistry, Mutant, Biology, Chromatin remodeling, Article, Epigenesis, Genetic, 03 medical and health sciences, Death-associated protein 6, alpha-Thalassemia, Glioma, Drug Discovery, medicine, Animals, Humans, Child, ATRX, Pharmacology, Telomere Homeostasis, medicine.disease, Chromatin Assembly and Disassembly, 030104 developmental biology, Histone, Mutation, biology.protein, Cancer research, Mental Retardation, X-Linked, Molecular Medicine, Function (biology)
Abstract

ATRX is a chromatin remodeling protein whose main function is the deposition of the histone variant H3.3. ATRX mutations are widely distributed in glioma, and correlate with alternative lengthening of telomeres (ALT) development, but they also affect other cellular functions related to epigenetic regulation. Areas covered: We discuss the main molecular characteristics of ATRX, from its various functions in normal development to the effects of its loss in ATRX syndrome patients and animal models. We focus on the salient consequences of ATRX mutations in cancer, from a clinical to a molecular point of view, focusing on both adult and pediatric glioma. Finally, we will discuss the therapeutic opportunities future research perspectives. Expert opinion: ATRX is a major component of various essential cellular pathways, exceeding its functions as a histone chaperone (e.g. DNA replication and repair, chromatin higher-order structure regulation, gene transcriptional regulation, etc.). However, it is unclear how the loss of these functions in ATRX-null cancer cells affects cancer development and progression. We anticipate new treatments and clinical approaches will emerge for glioma and other cancer types as mechanistic and molecular studies on ATRX are only just beginning to reveal the many critical functions of this protein in cancer.

Published
2018

19. Pathways Targeted by Antidiabetes Drugs Are Enriched for Multiple Genes Associated With Type 2 Diabetes Risk

Author

Nancy Wei, Ayellet V. Segrè, David Altshuler, Jose C. Florez, Magic Investigators, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Center for Liver, Digestive and Metabolic Diseases (CLDM)

Subjects
MECHANISM, Peroxisome proliferator-activated receptor gamma, SUSCEPTIBILITY LOCI, Genotype, endocrine system diseases, METFORMIN, medicine.drug_class, Endocrinology, Diabetes and Metabolism, Genome-wide association study, Type 2 diabetes, Polymorphism, Single Nucleotide, ABCC8, GLUCOSE, Databases, Genetic, GLYCEMIC TRAITS, Internal Medicine, medicine, Humans, Hypoglycemic Agents, Gene Regulatory Networks, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Thiazolidinedione, Gene, Genetic association, Genetics, INSULIN-RESISTANCE, biology, LARGE-SCALE ASSOCIATION, COMMON VARIANTS, nutritional and metabolic diseases, Genetics/Genomes/Proteomics/Metabolomics, medicine.disease, 3. Good health, Diabetes Mellitus, Type 2, Drug development, biology.protein, PPAR-GAMMA
Abstract

Genome-wide association studies (GWAS) have uncovered >65 common variants associated with type 2 diabetes (T2D); however, their relevance for drug development is not yet clear. Of note, the first two T2D-associated loci (PPARG and KCNJ11/ABCC8) encode known targets of antidiabetes medications. We therefore tested whether other genes/pathways targeted by antidiabetes drugs are associated with T2D. We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis (MAGENTA [Meta-Analysis Gene-set Enrichment of variaNT Associations]) to this gene set, using available GWAS meta-analyses for T2D and seven quantitative glycemic traits. We detected a strong enrichment of drug target genes associated with T2D (P = 2 × 10−5; 14 potential new associations), primarily driven by insulin and thiazolidinedione (TZD) targets, which was replicated in an independent meta-analysis (Metabochip). The glycemic traits yielded no enrichment. The T2D enrichment signal was largely due to multiple genes of modest effects (P = 4 × 10−4, after removing known loci), highlighting new associations for follow-up (ACSL1, NFKB1, SLC2A2, incretin targets). Furthermore, we found that TZD targets were enriched for LDL cholesterol associations, illustrating the utility of this approach in identifying potential side effects. These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design.

Published
2014

20. Differences in vascular endothelial growth factor receptor expression and correlation with the degree of enhancement in medulloblastoma

Author

Douglas J. Quint, Shawn L. Hervey-Jumper, Patricia L. Robertson, David Altshuler, Karin M. Muraszko, Hugh J. L. Garton, Darryl Lau, and Cormac O. Maher

Subjects
CD31, Medulloblastoma, Pathology, medicine.medical_specialty, biology, business.industry, Vascular Endothelial Growth Factor Receptor, VEGF receptors, General Medicine, Perioperative, medicine.disease, Metastasis, Vascular endothelial growth factor, Correlation, chemistry.chemical_compound, chemistry, biology.protein, Cancer research, medicine, business
Abstract

Object Vascular endothelial growth factor (VEGF) is the major proangiogenic factor in many solid tumors. Vascular endothelial growth factor receptor (VEGFR) is expressed in abundance in pediatric patients with medulloblastoma and is associated with tumor metastasis, poor prognosis, and proliferation. Gadolinium enhancement on MRI has been suggested to have prognostic significance for some tumors. The association of VEGF/VEGFR and Gd enhancement in medulloblastoma has never been closely examined. The authors therefore sought to evaluate whether Gd-enhancing medulloblastomas have higher levels of VEGFR and CD31. Outcomes and survival in patients with enhancing and nonenhancing tumors were also compared. Methods A retrospective analysis of patients with enhancing, nonenhancing, and partially enhancing medulloblastomas was performed. Primary end points included risk stratification, extent of resection, and perioperative complications. A cohort of 3 enhancing and 3 nonenhancing tumors was selected for VEGFR and CD31 analysis as well as microvessel density measurements. Results Fifty-eight patients were analyzed, and 20.7% of the medulloblastomas in these patients were nonenhancing. Enhancing medulloblastomas exhibited strong VEGFR1/2 and CD31 expression relative to nonenhancing tumors. There was no significant difference in perioperative complications or patient survival between the 2 groups. Conclusions These results suggest that in patients with medulloblastoma the presence of enhancement on MRI may correlate with increased vascularity and angiogenesis, but does not correlate with worse patient prognosis in the short or long term.

Published
2014

21. Key determinants of short-term and long-term glioblastoma survival: A 14-year retrospective study of patients from the Hermelin Brain Tumor Center at Henry Ford Hospital

Author

Lonni Schultz, Laila M. Poisson, Steven N. Kalkanis, Tom Mikkelsen, Rajan Jain, Mark L. Rosenblum, Xin Hong, David Altshuler, and Paul Mazaris

Subjects
Male, Oncology, medicine.medical_specialty, Time Factors, Multivariate analysis, medicine.medical_treatment, Brain tumor, Internal medicine, medicine, Humans, Neoplasm, Karnofsky Performance Status, Aged, Retrospective Studies, Chemotherapy, Performance status, business.industry, Retrospective cohort study, General Medicine, Middle Aged, medicine.disease, Survival Analysis, Surgery, Radiation therapy, Disease Progression, Female, Neurology (clinical), Glioblastoma, business
Abstract

Objective Glioblastoma (GBM) is a heterogeneous neoplasm with a small percentage of long-term survivors. Despite aggressive surgical resection and advances in radiotherapy and chemotherapy, the median survival for patients with GBM is 12–14 months. Factors associated with a favorable prognosis include young age, high performance status, gross resection >98%, non-eloquent tumor location and O6-methylguanine methyltransferase (MGMT) promoter methylation. We retrospectively analyzed the relationship of clinical, epidemiologic, genetic and molecular characteristics with survival in patients with GBM. Methods This retrospective analysis of overall survival looked at the outcomes of 480 patients diagnosed with GBM over 14 years at a single institution. Multivariate analysis was performed examining multiple patient characteristics. Results Median survival time improved from 11.8 months in patients diagnosed from 1995 to 1999 to 15.9 months in those diagnosed from 2005 to 2008. Factors associated with survivor groups were age, KPS, tumor resection, treatment received and early progression. 18 cancer-related genes were upregulated in short-term survivors and five genes were downregulated in short-term survivors. Conclusions Epidemiologic, clinical, and molecular characteristics all contribute to GBM prognosis. Identifying factors associated with survival is important for treatment strategies as well as research for novel therapeutics and technologies. This study demonstrated improved survival for patients over time as well as significant differences among survivor groups.

Published
2014

22. Increased Burden of Cardiovascular Disease in Carriers of APOL1 Genetic Variants

Author

Steven R. DePalma, Kaoru Ito, Christopher Newton-Cheh, Jason Flannick, Jonathan G. Seidman, Namrata Gupta, David J. Friedman, Sekar Kathiresan, James G. Wilson, Alexander G. Bick, Martin R. Pollak, Giulio Genovese, Christine E. Seidman, Stacey Gabriel, Michael Parfenov, David Altshuler, Ervin R. Fox, Joel N. Hirschhorn, and Herman A. Taylor

Subjects
Genetics, education.field_of_study, medicine.medical_specialty, biology, Physiology, Apolipoprotein L1, business.industry, Population, Disease, medicine.disease, Internal medicine, Genotype, Genetic variation, Epidemiology, biology.protein, Medicine, Allele, Cardiology and Cardiovascular Medicine, education, business, Kidney disease
Abstract

Rationale: Two distinct alleles in the gene encoding apolipoprotein L1 ( APOL1 ), a major component of high-density lipoprotein, confer protection against Trypanosoma brucei rhodesiense infection and also increase risk for chronic kidney disease. Approximately 14% of Americans with African ancestry carry 2 APOL1 risk alleles, accounting for the high chronic kidney disease burden in this population. Objective: We tested whether APOL1 risk alleles significantly increase risk for atherosclerotic cardiovascular disease (CVD) in African Americans. Methods and Results: We sequenced APOL1 in 1959 randomly selected African American participants in the Jackson Heart Study (JHS) and evaluated associations between APOL1 genotypes and renal and cardiovascular phenotypes. Previously identified association between APOL1 genotypes and chronic kidney disease was confirmed ( P =2.4×10 −6 ). Among JHS participants with 2 APOL1 risk alleles, we observed increased risk for CVD (50/763 events among participants without versus 37/280 events among participants with 2 risk alleles; odds ratio, 2.17; P =9.4×10 −4 ). We replicated this novel association of APOL1 genotype with CVD in Women’s Health Initiative (WHI) participants (66/292 events among participants without versus 37/101 events among participants with 2 risk alleles; odds ratio, 1.98; P =8.37×10 −3 ; JHS and WHI combined, P =8.5×10 −5 ; odds ratio, 2.12). The increased risk for CVD conferred by APOL1 alleles was robust to correction for both traditional CVD risk factors and chronic kidney disease. Conclusions: APOL1 variants contribute to atherosclerotic CVD risk, indicating a genetic component to cardiovascular health disparities in individuals of African ancestry. The considerable population of African Americans with 2 APOL1 risk alleles may benefit from intensive interventions to reduce CVD.

Published
2014

23. First in Human Phase I Trial of Dual Vector (HSV1-TK, Flt3L) Immunotherapy For The Treatment of Newly Diagnosed High-Grade Glioma: Initial Results

Author

Karin M. Muraszko, Michelle M. Kim, Lilli Zhao, Yoshie Umemura, Paul E. McKeever, David Altshuler, Karen Sagher, Daniel Zamler, Andrew P. Lieberman, Vivek Yadav, Larry Junck, Daniel A. Orringer, Andrea Comba, Sandra Camelo-Piragua, Oren Sagher, Pedro R. Lowenstein, Sriram Venneti, Patrick Dunn, D.R. Wahl, Jason Heth, Aaron Mammoser, Theodore Lawrence, Kait Verbal, Maria G. Castro, Denise Leung, and Shawn L. Hervey-Jumper

Subjects
Oncology, medicine.medical_specialty, business.industry, medicine.medical_treatment, Newly diagnosed, Immunotherapy, First in human, medicine.disease, Internal medicine, Glioma, medicine, Combined Modality Therapy, Surgery, Neurology (clinical), Vector (molecular biology), Progression-free survival, business, High-Grade Glioma
Published
2019

24. First-in-human phase I trial of the combination of two adenoviral vectors expressing HSV1-TK and FLT3L for the treatment of newly diagnosed resectable malignant glioma: Initial results from the therapeutic reprogramming of the brain immune system

Author

Sriram Venneti, Jason Heth, Sandra Camelo-Piragua, Karin M. Muraszko, Michelle M. Kim, Theodore S. Lawrence, Andrew P. Lieberman, Larry Junck, Maria G. Castro, Denise Leung, Daniel A. Orringer, Daniel R. Wahl, Pedro R. Lowenstein, Yoshie Umemura, Andrea Comba, Paul E. McKeever, Aaron Mammoser, Shawn L. Hervey-Jumper, David Altshuler, and Oren Sagher

Subjects
Cancer Research, business.industry, First in human, Newly diagnosed, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Immune system, Oncology, 030220 oncology & carcinogenesis, Glioma, medicine, Cancer research, Dose escalation, business, Reprogramming, 030215 immunology
Abstract

2019 Background: This is the initial report on a first in human Phase I dose escalation trial of the combination of two adenoviral vectors expressing HSV1-TK or Flt3L for the treatment of newly diagnosed, resectable malignant gliomas. The absence of functional dendritic cells from the brain precludes anti-brain tumor immune responses. We combined tumor cytotoxicity (Ad-HSV1TK) with recruitment of dendritic cells to the brain (Ad-Flt3L) to induce an effective anti-tumor immune response. This strategy induced an efficacious, cytotoxic CD8 and CD4 T-dependent immune response in many animal models of glioma. This immune response also generated anti-tumor memory, and the capacity for neoantigen recognition. Methods: The trial was approved by FDA and all institutional cttees. Treatment was administered intraoperatively following complete glioma resection in newly diagnosed tumors. The trial consisted of vector dose escalation, starting at 1x10^9 i.u., and increasing to 1x10^11 i.u. of each vector. Dose escalation proceeded by increasing the vector dose through a total of 6 combinations administered to 6 cohorts of 3 patients each. Two cycles of 14 days each of valacyclovir were administered to activate HSV1-TK cytotoxicity. Cycle 1 starts on Day 1-3 post surgery for 14 days, and Cycle 2 on Week 8-12. Standard radiation, i.e., 60 Gy in 2 Gy fractions over 6 weeks, with concurrent temozolomide, was followed by cyclic temozolomide. Results: Examination of tumor samples at primary resection and first recurrence show an increase in the infiltration of inflammatory cells. The experimental treatment was well tolerated. At this time the MTD has not been reached. There were approx. 248 AEs, and 26 SAEs; these have not been linked to treatment. At this time the MTD has not been reached. A secondary outcome is overall survival. Preliminary analysis of partial data may suggest that the combined viral vector therapy may provide a clinically significant survival. Conclusions: Our results show for the first time that reprogramming of the host’s brain immune system to recognize gliomas reveals a new approach for the treatment of highly malignant brain tumors. Clinical trial information: NCT01811992.

Published
2019

25. Common variants associated with plasma triglycerides and risk for coronary artery disease

Author

Richard S. Cooper, Angela Döring, Cisca Wijmenga, Jerome I. Rotter, Linda S. Adair, Tõnu Esko, Jennifer L. Bragg-Gresham, Danish Saleheen, Narisu Narisu, Xiaohui Li, Kathleen Stirrups, Ulf de Faire, Nicholas G. Martin, Dmitry Shungin, Peter Vollenweider, Yii-Der Ida Chen, Dharambir K. Sanghera, George Dedoussis, Toshiko Tanaka, Manjinder S. Sandhu, Anne U. Jackson, Nancy L. Pedersen, Maria Dimitriou, Shih-Yi Lin, David P. Strachan, Isleifur Olafsson, Ruth J. F. Loos, Kay-Tee Khaw, Antero Kesäniemi, Rainer Rauramaa, Wendy L. McArdle, Gonneke Willemsen, Dena G. Hernandez, May E. Montasser, Amy J. Swift, Colin A. McKenzie, Aaron Isaacs, Latonya F. Been, Leif Groop, Massimo Mangino, Martina Müller-Nurasyid, Karen L. Mohlke, Ci Song, Sailaja Vedantam, Anna-Liisa Hartikainen, Lori L. Bonnycastle, Ilja M. Nolte, Jaakko Kaprio, Anneli Pouta, Unnur Thorsteinsdottir, Paul Elliott, Muredach P. Reilly, Jean Ferrières, Daniel J. Rader, Elizabeth H. Young, Jaspal S. Kooner, Leena Moilanen, Markku Laakso, Albert Hofman, Kelly A. Volcik, Sekar Kathiresan, Tamara B. Harris, Eric Kim, Aimo Ruokonen, Andrea Ganna, Serena Sanna, John J.P. Kastelein, Martha L. Gravito, Ronald M. Krauss, Ken K. Ong, Paul M. Ridker, Kristian Hveem, Ayse Demirkan, Alena Stančáková, Pierre Meneton, Thomas Quertermous, John Danesh, Toby Johnson, Cornelia M. van Duijn, Samuli Ripatti, Christopher J. Groves, Jaakko Tuomilehto, Michael Boehnke, Jose M. Ordovas, Alan B. Feranil, Chao A. Hsiung, Wayne Huey-Herng Sheu, Igor Rudan, Christa Meisinger, Rebecca N. Nsubuga, Bruna Gigante, Inger Njølstad, Göran Hallmans, Aroon D. Hingorani, Jouko Saramies, Deepti Gurdasani, Fernando Rivadeneira, Andres Metspalu, Stephen E. Epstein, Gonçalo R. Abecasis, Braxton D. Mitchell, Devin Absher, Marcus E. Kleber, Sonia Shah, Pierre Fontanillas, Jeffrey R. O'Connell, Louise A. Donnelly, Jing Hua Zhao, Martin L. Buchkovich, Francis S. Collins, Gabrielle Müller, Matti Uusitupa, Evelin Mihailov, Nicholas J. Wareham, Andrew A. Hicks, Dorret I. Boomsma, Harry Campbell, Ellen M. Schmidt, Jaana Lindström, Mark I. McCarthy, Evita G. Van Den Herik, Kirsten Ohm Kyvik, Vilmundur Gudnason, Jackie F. Price, Joel N. Hirschhorn, Winfried März, Aravinda Chakravarti, Pontiano Kaleebu, James F. Wilson, Lindsay L. Waite, Leo-Pekka Lyytikäinen, Sebanti Sengupta, Mika Kivimäki, David Altshuler, Hilma Holm, Rona J. Strawbridge, Harald Grallert, Ramaiah Nagaraja, Laurence Tiret, G. Kees Hovingh, Meena Kumari, Nilesh J. Samani, Daniel F. Freitag, Nelson B. Freimer, Thomas Illig, Panos Deloukas, Bernhard O. Boehm, Nicholas W.J. Wainwright, Mark J. Daly, Mika Kähönen, Michel Burnier, Norman Klopp, L. Adrienne Cupples, Aarno Palotie, Markus Perola, Bamidele O. Tayo, Timo A. Lakka, Matthew Jones, Sarah H. Wild, Patricia B. Munroe, Antti Jula, François Mach, Peter J. Koudstaal, Pirjo Komulainen, Eric Boerwinkle, L. Joost van Pelt, Veikko Salomaa, Ann-Kristin Petersen, Ida Surakka, Andrew Wong, Caroline Hayward, Chi Gao, Cristen J. Willer, Stephen S. Rich, Yi Jen Hung, Peter P. Pramstaller, Diana Kuh, Ron Do, Dominique Arveiler, Mark O. Goodarzi, Ross M. Fraser, Ingrid B. Borecki, Steven C. Hunt, Weihua Zhang, Mary Susan Burnett, Patrik K. E. Magnusson, John C. Chambers, Benjamin M. Neale, Peter Schwarz, Jennifer L. Bolton, Murielle Bochud, Heleen M. den Hertog, Christian Gieger, Cristina Pomilla, Teresa Ferreira, Lars Wallentin, Richa Saxena, André G. Uitterlinden, Kaisa Silander, Ying Wu, Bruce M. Psaty, Jian'an Luan, Hsing-Yi Chang, Jin Chen, Daniel I. Chasman, Ulf Gyllensten, Kari Stefansson, Kauko Heikkilä, Tom Wilsgaard, Alan R. Shuldiner, Carlos Iribarren, Stavroula Kanoni, John Whitfield, Gershim Asiki, Marika Kaakinen, Georg Ehret, Elina Hyppönen, Claudia Langenberg, Gina M. Peloso, Cecilia M. Lindgren, Carlo Sidore, Gudmundur I. Eyjolfsson, Cameron D. Palmer, Jacques S. Beckmann, Hubert Scharnagl, Tanya M. Teslovich, Mary F. Feitosa, Terho Lehtimäki, Steve E. Humphries, Chris Power, Benjamin F. Voight, Stefania Bandinelli, Andrew D. Morris, Gudmar Thorleifsson, Tuomo Nieminen, Tim D. Spector, Paul W. Franks, Themistocles L. Assimes, Pascal Bovet, Luigi Ferrucci, Johannes Kettunen, Inês Barroso, Franklyn I. Bennett, Stefan Gustafsson, Paolo Brambilla, Theodore Papamarkou, Elena Tremoli, Janet Seeley, Alex S. F. Doney, Johanna Kuusisto, Giancarlo Cesana, Bruce H. R. Wolffenbuttel, Lars Lind, Stefan R. Bornstein, Åsa Johansson, Anders Hamsten, Marjo-Riitta Järvelin, Krista Fischer, Agneta Siegbahn, Samia Mora, Erik Ingelsson, Colin N. A. Palmer, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Epidemiology, Surgery, Public Health, Ophthalmology, Neurology, Medical Microbiology & Infectious Diseases, Obstetrics & Gynecology, Internal Medicine, Do, Ron, Willer, Cristen J, Schmidt, Ellen M, Sengupta, Sebanti, Hyppönen, Elina, Kathiresan, Sekar, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Do, R, Willer, C, Schmidt, E, Sengupta, S, Gao, C, Peloso, G, Gustafsson, S, Kanoni, S, Ganna, A, Chen, J, Buchkovich, M, Mora, S, Beckmann, J, Bragg Gresham, J, Chang, H, Demirkan, A, Den Hertog, H, Donnelly, L, Ehret, G, Esko, T, Feitosa, M, Ferreira, T, Fischer, K, Fontanillas, P, Fraser, R, Freitag, D, Gurdasani, D, Heikkilä, K, Hyppönen, E, Isaacs, A, Jackson, A, Johansson, A, Johnson, T, Kaakinen, M, Kettunen, J, Kleber, M, Li, X, Luan, J, Lyytikäinen, L, Magnusson, P, Mangino, M, Mihailov, E, Montasser, M, Müller Nurasyid, M, Nolte, I, O'Connell, J, Palmer, C, Perola, M, Petersen, A, Sanna, S, Saxena, R, Service, S, Shah, S, Shungin, D, Sidore, C, Song, C, Strawbridge, R, Surakka, I, Tanaka, T, Teslovich, T, Thorleifsson, G, Van den Herik, E, Voight, B, Volcik, K, Waite, L, Wong, A, Wu, Y, Zhang, W, Absher, D, Asiki, G, Barroso, I, Been, L, Bolton, J, Bonnycastle, L, Brambilla, P, Burnett, M, Cesana, G, Dimitriou, M, Doney, A, Döring, A, Elliott, P, Epstein, S, Eyjolfsson, G, Gigante, B, Goodarzi, M, Grallert, H, Gravito, M, Groves, C, Hallmans, G, Hartikainen, A, Hayward, C, Hernandez, D, Hicks, A, Holm, H, Hung, Y, Illig, T, Jones, M, Kaleebu, P, Kastelein, J, Khaw, K, Kim, E, Klopp, N, Komulainen, P, Kumari, M, Langenberg, C, Lehtimäki, T, Lin, S, Lindström, J, Loos, R, Mach, F, Mcardle, W, Meisinger, C, Mitchell, B, Müller, G, Nagaraja, R, Narisu, N, Nieminen, T, Nsubuga, R, Olafsson, I, Ong, K, Palotie, A, Papamarkou, T, Pomilla, C, Pouta, A, Rader, D, Reilly, M, Ridker, P, Rivadeneira, F, Rudan, I, Ruokonen, A, Samani, N, Scharnagl, H, Seeley, J, Silander, K, Stančáková, A, Stirrups, K, Swift, A, Tiret, L, Uitterlinden, A, van Pelt, L, Vedantam, S, Wainwright, N, Wijmenga, C, Wild, S, Willemsen, G, Wilsgaard, T, Wilson, J, Young, E, Zhao, J, Adair, L, Arveiler, D, Assimes, T, Bandinelli, S, Bennett, F, Bochud, M, Boehm, B, Boomsma, D, Borecki, I, Bornstein, S, Bovet, P, Burnier, M, Campbell, H, Chakravarti, A, Chambers, J, Chen, Y, Collins, F, Cooper, R, Danesh, J, Dedoussis, G, de Faire, U, Feranil, A, Ferrières, J, Ferrucci, L, Freimer, N, Gieger, C, Groop, L, Gudnason, V, Gyllensten, U, Hamsten, A, Harris, T, Hingorani, A, Hirschhorn, J, Hofman, A, Hovingh, G, Hsiung, C, Humphries, S, Hunt, S, Hveem, K, Iribarren, C, Järvelin, M, Jula, A, Kähönen, M, Kaprio, J, Kesäniemi, A, Kivimaki, M, Kooner, J, Koudstaal, P, Krauss, R, Kuh, D, Kuusisto, J, Kyvik, K, Laakso, M, Lakka, T, Lind, L, Lindgren, C, Martin, N, März, W, Mccarthy, M, Mckenzie, C, Meneton, P, Metspalu, A, Moilanen, L, Morris, A, Munroe, P, Njølstad, I, Pedersen, N, Power, C, Pramstaller, P, Price, J, Psaty, B, Quertermous, T, Rauramaa, R, Saleheen, D, Salomaa, V, Sanghera, D, Saramies, J, Schwarz, P, Sheu, W, Shuldiner, A, Siegbahn, A, Spector, T, Stefansson, K, Strachan, D, Tayo, B, Tremoli, E, Tuomilehto, J, Uusitupa, M, van Duijn, C, Vollenweider, P, Wallentin, L, Wareham, N, Whitfield, J, Wolffenbuttel, B, Altshuler, D, Ordovas, J, Boerwinkle, E, Thorsteinsdottir, U, Chasman, D, Rotter, J, Franks, P, Ripatti, S, Cupples, L, Sandhu, M, Rich, S, Boehnke, M, Deloukas, P, Mohlke, K, Ingelsson, E, Abecasis, G, Daly, M, Neale, B, and Kathiresan, S

Subjects
Netherlands Twin Register (NTR), BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Heart disease, Genome-wide association study, Coronary Artery Disease, 030204 cardiovascular system & hematology, ISCHEMIC-HEART-DISEASE, Triglyceride, Coronary artery disease, chemistry.chemical_compound, 0302 clinical medicine, High-density lipoprotein, Polymorphism (computer science), Risk Factors, High-density-lipoprotein, Genetic epidemiology, 11 Medical and Health Sciences, Genetics & Heredity, 0303 health sciences, Cholesterol, HDL/blood, Cholesterol levels, Loci, Contribute, Single Nucleotide, LDL/blood, Triglycerides/blood, Cholesterol, Cholesterol, LDL/blood, HDL/blood, lipids (amino acids, peptides, and proteins), Life Sciences & Biomedicine, Human, medicine.medical_specialty, TYPE-2 DIABETES-MELLITUS, Biology, Polymorphism, Single Nucleotide, Article, HIGH-DENSITY-LIPOPROTEIN ISCHEMIC-HEART-DISEASE TYPE-2 DIABETES-MELLITUS MENDELIAN RANDOMIZATION CARDIOVASCULAR-DISEASE GENETIC EPIDEMIOLOGY CHOLESTEROL LEVELS LOCI CONTRIBUTE THERAPY, 03 medical and health sciences, Coronary Artery Disease/blood, SDG 3 - Good Health and Well-being, Cardiovascular-disease, Internal medicine, Mendelian randomization, Genetics, medicine, Humans, Polymorphism, plasma, Triglycerides, 030304 developmental biology, Science & Technology, Risk Factor, Cholesterol, HDL, Biological Transport, Cholesterol, LDL, 06 Biological Sciences, medicine.disease, Heart-disease, lipoproteins, Endocrinology, chemistry, Therapy, Developmental Biology
Abstract

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10 -8 for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD. © 2013 Nature America, Inc. All rights reserved.

Published
2013

26. Rare Complete Knockouts in Humans: Population Distribution and Significant Role in Autism Spectrum Disorders

Author

Richard A. Gibbs, Shaun Purcell, Stephen Sanders, Bernie Devlin, Li Liu, Andrew Kirby, Chiao-Feng Lin, Elaine T. Lim, Shannon Gross, Eric Boerwinkle, Huyen Dinh, Jeffrey G. Reid, Jason Flannick, Monkol Lek, Alicia Hawes, Matthew W. State, Li-San Wang, Lora Lewis, Joseph D. Buxbaum, Kathryn Roeder, Edwin H. Cook, Uma Nagaswamy, Mark A. DePristo, Gerard D. Schellenberg, Mark J. Daly, David Altshuler, Irene Newsham, Christine Stevens, Stephan Ripke, Menachem Fromer, Yuanqing Wu, Benjamin M. Neale, Soumya Raychaudhuri, Stacey Gabriel, Donna M. Muzny, Aniko Sabo, Daniel G. MacArthur, James S. Sutcliffe, Otto Valladares, and Douglas M. Ruderfer

Subjects
Proband, Genetics, 0303 health sciences, education.field_of_study, Neuroscience(all), General Neuroscience, Population, Pseudoautosomal region, Biology, Compound heterozygosity, medicine.disease, Article, 03 medical and health sciences, 0302 clinical medicine, medicine, Autism, education, 030217 neurology & neurosurgery, Gene knockout, X chromosome, Exome sequencing, 030304 developmental biology
Abstract

SummaryTo characterize the role of rare complete human knockouts in autism spectrum disorders (ASDs), we identify genes with homozygous or compound heterozygous loss-of-function (LoF) variants (defined as nonsense and essential splice sites) from exome sequencing of 933 cases and 869 controls. We identify a 2-fold increase in complete knockouts of autosomal genes with low rates of LoF variation (≤5% frequency) in cases and estimate a 3% contribution to ASD risk by these events, confirming this observation in an independent set of 563 probands and 4,605 controls. Outside the pseudoautosomal regions on the X chromosome, we similarly observe a significant 1.5-fold increase in rare hemizygous knockouts in males, contributing to another 2% of ASDs in males. Taken together, these results provide compelling evidence that rare autosomal and X chromosome complete gene knockouts are important inherited risk factors for ASD.

Published
2013

27. Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms

Author

Victor Rusu, Eitan Hoch, Josep M. Mercader, Danielle E. Tenen, Melissa Gymrek, Christina R. Hartigan, Michael DeRan, Marcin von Grotthuss, Pierre Fontanillas, Alexandra Spooner, Gaelen Guzman, Amy A. Deik, Kerry A. Pierce, Courtney Dennis, Clary B. Clish, Steven A. Carr, Bridget K. Wagner, Monica Schenone, Maggie C.Y. Ng, Brian H. Chen, Federico Centeno-Cruz, Carlos Zerrweck, Lorena Orozco, David M. Altshuler, Stuart L. Schreiber, Jose C. Florez, Suzanne B.R. Jacobs, Eric S. Lander, Daniel Shriner, Jiang Li, Wei-Min Chen, Xiuqing Guo, Jiankang Liu, Suzette J. Bielinski, Lisa R. Yanek, Michael A. Nalls, Mary E. Comeau, Laura J. Rasmussen-Torvik, Richard A. Jensen, Daniel S. Evans, Yan V. Sun, Ping An, Sanjay R. Patel, Yingchang Lu, Jirong Long, Loren L. Armstrong, Lynne Wagenknecht, Lingyao Yang, Beverly M. Snively, Nicholette D. Palmer, Poorva Mudgal, Carl D. Langefeld, Keith L. Keene, Barry I. Freedman, Josyf C. Mychaleckyj, Uma Nayak, Leslie J. Raffel, Mark O. Goodarzi, Y-D Ida Chen, Herman A. Taylor, Adolfo Correa, Mario Sims, David Couper, James S. Pankow, Eric Boerwinkle, Adebowale Adeyemo, Ayo Doumatey, Guanjie Chen, Rasika A. Mathias, Dhananjay Vaidya, Andrew B. Singleton, Alan B. Zonderman, Robert P. Igo, John R. Sedor, Edmond K. Kabagambe, David S. Siscovick, Barbara McKnight, Kenneth Rice, Yongmei Liu, Wen-Chi Hsueh, Wei Zhao, Lawrence F. Bielak, Aldi Kraja, Michael A. Province, Erwin P. Bottinger, Omri Gottesman, Qiuyin Cai, Wei Zheng, William J. Blot, William L. Lowe, Jennifer A. Pacheco, Dana C. Crawford, Elin Grundberg, Stephen S. Rich, M. Geoffrey Hayes, Xiao-Ou Shu, Ruth J.F. Loos, Ingrid B. Borecki, Patricia A. Peyser, Steven R. Cummings, Bruce M. Psaty, Myriam Fornage, Sudha K. Iyengar, Michele K. Evans, Diane M. Becker, W.H. Linda Kao, James G. Wilson, Jerome I. Rotter, Michèle M. Sale, Simin Liu, Charles N. Rotimi, Donald W. Bowden, Alicia Huerta-Chagoya, Humberto García-Ortiz, Hortensia Moreno-Macías, Alisa Manning, Lizz Caulkins, Noël P. Burtt, Jason Flannick, Nick Patterson, Carlos A. Aguilar-Salinas, Teresa Tusié-Luna, David Altshuler, Angélica Martínez-Hernández, Francisco Martin Barajas-Olmos, Cecilia Contreras-Cubas, Elvia Mendoza-Caamal, Cristina Revilla-Monsalve, Sergio Islas-Andrade, Emilio Córdova, Xavier Soberón, Clicerio González-Villalpando, María Elena González-Villalpando, Christopher A. Haiman, Lynne Wilkens, Loic Le Marchand, Kristine Monroe, Laurence Kolonel, Olimpia Arellano-Campos, Maria L. Ordóñez-Sánchez, Maribel Rodríguez-Torres, Yayoi Segura-Kato, Rosario Rodríguez-Guillén, Ivette Cruz-Bautista, Linda Liliana Muñoz-Hernandez, Tamara Sáenz, Donají Gómez, Ulices Alvirde, Paloma Almeda-Valdés, Maria L. Cortes, Massachusetts Institute of Technology. Department of Biology, Altshuler, David M, and Lander, Eric Steven

Subjects
0301 basic medicine, Models, Molecular, Monocarboxylic Acid Transporters, Heterozygote, endocrine system diseases, Locus (genetics), Type 2 diabetes, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Allele, Monocarboxylate transporter, Genetics, biology, Haplotype, Cell Membrane, nutritional and metabolic diseases, Lipid metabolism, Heterozygote advantage, medicine.disease, Histone Code, 030104 developmental biology, Diabetes Mellitus, Type 2, Haplotypes, Liver, Basigin, Gene Knockdown Techniques, biology.protein, Hepatocytes, 030217 neurology & neurosurgery, Chromosomes, Human, Pair 17
Abstract

Type 2 diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype spanning SLC16A11 that explains ∼20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly linked variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreasing SLC16A11 expression in liver and (2) disrupting a key interaction with basigin, thereby reducing cell-surface localization. Both independent mechanisms reduce SLC16A11 function and suggest SLC16A11 is the causal gene at this locus. To gain insight into how SLC16A11 disruption impacts T2D risk, we demonstrate that SLC16A11 is a proton-coupled monocarboxylate transporter and that genetic perturbation of SLC16A11 induces changes in fatty acid and lipid metabolism that are associated with increased T2D risk. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D. Video Abstract [Figure presented] Keywords: type 2 diabetes (T2D); genetics; disease mechanism; SLC16A11; MCT11; solute carrier (SLC); monocarboxylates; fatty acid metabolism; lipid metabolism; precision medicine

Published
2016

28. Common variants at 30 loci contribute to polygenic dyslipidemia

Author

Michael Boehnke, Luigi Ferrucci, Aarti Surti, Jaakko Tuomilehto, Karen L. Mohlke, Candace Guiducci, Lee M. Kaplan, Rory Collins, Leena Peltonen, Qiong Yang, Cristen J. Willer, Francis S. Collins, Angelo Scuteri, Christopher J. O'Donnell, Edward G. Lakatta, Serkalem Demissie, Johanna Kuusisto, John C. Chambers, Amy J. Swift, Leif Groop, Markku Laakso, Gina M. Peloso, Sekar Kathiresan, Jouko Sundvall, G. Mark Lathrop, Gonçalo R. Abecasis, Benjamin F. Voight, Jose M. Ordovas, Veikko Salomaa, Eric E. Schadt, Robert Clarke, David Altshuler, David Schlessinger, Diana Zelenika, Pilar Galan, Serge Hercberg, Derrick A Bennett, Kari Kubalanza, Laura J. Scott, Kiran Musunuru, Kathryn L. Lunetta, Serena Sanna, Marju Orho-Melander, L. Adrienne Cupples, Toshiko Tanaka, Gabriel Crawford, Pierre Meneton, Josée Dupuis, Anne U. Jackson, Sarah Parish, Paul I.W. de Bakker, Yun Li, Olle Melander, Mario A. Morken, Manuela Uda, Heather M. Stringham, Lori L. Bonnycastle, Noël P. Burtt, Paul Scheet, Richard N. Bergman, and Jaspal S. Kooner

Subjects
Adult, Male, Multifactorial Inheritance, medicine.medical_specialty, Quantitative Trait Loci, Blood lipids, Genome-wide association study, 030204 cardiovascular system & hematology, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, chemistry.chemical_compound, Delta-5 Fatty Acid Desaturase, 0302 clinical medicine, Meta-Analysis as Topic, ANGPTL4, Internal medicine, Genetics, medicine, Humans, RNA, Messenger, Allele, Alleles, Triglycerides, Dyslipidemias, 030304 developmental biology, 0303 health sciences, Triglyceride, Cholesterol, Cholesterol, HDL, Reproducibility of Results, Cholesterol, LDL, Syndrome, Middle Aged, medicine.disease, 3. Good health, Phenotype, Endocrinology, Gene Expression Regulation, Liver, chemistry, Female, lipids (amino acids, peptides, and proteins), Dyslipidemia, Genome-Wide Association Study, Lipoprotein
Abstract

Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P < 5 x 10(-8)), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P < 10(-15) for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.

Published
2016

29. A null mutation in ANGPTL8 does not associate with either plasma glucose or type 2 diabetes in humans

Author

Roxana Mehran, Michael Boehnke, Valentin Fuster, Manuel A. Rivas, Jason Flannick, Mark I. McCarthy, Daniel J. Rader, Pradeep Natarajan, Jennifer Wessel, Robert A. Scott, Audrey Y. Chu, Katharine R. Clapham, Samantha Sartori, Sekar Kathiresan, Gina M. Peloso, David Altshuler, and Usman Baber

Subjects
0301 basic medicine, Blood Glucose, Male, medicine.medical_specialty, Betatrophin, Endocrinology, Diabetes and Metabolism, Peptide Hormones, Type 2 diabetes, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Polymorphism (computer science), Angiopoietin-Like Protein 8, Internal medicine, Diabetes mellitus, medicine, Glucose homeostasis, Humans, Point Mutation, Angiopoietin-like 8, Genetic Association Studies, Glucose tolerance test, medicine.diagnostic_test, business.industry, Case-control study, General Medicine, Glucose Tolerance Test, medicine.disease, rs145464906, Null allele, Lipids, 030104 developmental biology, Endocrinology, Angiopoietin-like Proteins, Phenotype, Diabetes Mellitus, Type 2, Case-Control Studies, Female, business, Research Article
Abstract

Background Experiments in mice initially suggested a role for the protein angiopoietin-like 8 (ANGPTL8) in glucose homeostasis. However, subsequent experiments in model systems have challenged this proposed role. We sought to better understand the importance of ANGPTL8 in human glucose homeostasis by examining the association of a null mutation in ANGPTL8 with fasting glucose levels and risk for type 2 diabetes. Methods A naturally-occurring null mutation in human ANGPTL8 (rs145464906; c.361C > T; p.Q121X) is carried by ~1 in 1000 individuals of European ancestry and is associated with higher levels of plasma high-density lipoprotein cholesterol, suggesting that this mutation has functional significance. We examined the association of p.Q121X with fasting glucose levels and risk for type 2 diabetes in up to 95,558 individuals (14,824 type 2 diabetics and 80,734 controls). Results We found no significant association of p.Q121X with either fasting glucose or type 2 diabetes (p-value = 0.90 and 0.65, respectively). Given our sample sizes, we had >98 % power to detect at least a 0.23 mmol/L effect on plasma glucose and >95 % power to detect a 70 % increase in risk for type 2 diabetes. Conclusion Disruption of ANGPTL8 function in humans does not seem to have a large effect on measures of glucose tolerance. Electronic supplementary material The online version of this article (doi:10.1186/s12902-016-0088-8) contains supplementary material, which is available to authorized users.

Published
2016

30. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Author

Peter Kovacs, Alan F. Wright, Stephen Turner, Michèle M. Sale, Siim Sõber, Janoš Terzić, Elin Org, Richard S. Cooper, Alena Stančáková, Jerome I. Rotter, W. H. Linda Kao, Albert Hofman, Andrew B. Singleton, Florian Kronenberg, Jianjun Liu, Nicole L. Glazer, Christopher W. Knouff, Jennifer L. Bragg-Gresham, Juha Karjalainen, Li Ching Chang, Benjamin J. Wright, Jacqueline C.M. Witteman, Martin G. Larson, Klaus Stark, Richard J. Rodeheffer, Sharon L.R. Kardia, Douglas M. Ruderfer, Sheila Ulivi, Madhumathi Rao, Andrew A. Hicks, Eva Brand, Viviane Nicaud, Stephen G. Ball, Anna Köttgen, Germaine C. Verwoert, Anders Hamsten, Nick Shrine, Uwe Völker, Stefan Kloiber, Stephen Hancock, Emelia J. Benjamin, Bok Ghee Han, Kenneth Rice, Mark Woodward, Veronique Vitart, Karl Andersen, Nicholas J. Wareham, Robert Roberts, Maja Barbalić, David Couper, Yukinori Okada, André G. Uitterlinden, Sekar Kathiresan, Leo-Pekka Lyytikäinen, Pankaj Arora, Tatijana Zemunik, David S. Siscovick, Simonetta Guarrera, Dawn M. Waterworth, Tatjana Stojakovic, Braxton D. Mitchell, Devin Absher, Carmen A. Peralta, Mika Kivimäki, Xueling Sim, Norihiro Kato, Philippe Froguel, Keith L. Keene, Donna K. Arnett, Naoyuki Kamatani, Tazeen H. Jafar, Idris Guessous, Gunnar Jacobs, Michael M. Hoffmann, Kari Stefansson, Christian Hengstenberg, Tomonori Okamura, Inga Prokopenko, Christina Willenborg, Peter S. Braund, Rainer Rettig, Francesco U.S. Mattace-Raso, Vikal Tripathy, F. Gerald R. Fowkes, Laura R. Loehr, Harry Campbell, Margherita Cavalieri, Olle Melander, Hao Mei, I. Mateo Leach, Nicholette D. Palmer, Eva Albrecht, Naoharu Iwai, Stefan Martin Brand, Toshiko Tanaka, Jackie A. Cooper, Omri Gottesman, Manuela Uda, Angelo Scuteri, Aroon D. Hingorani, Cristiano Fava, Yusuke Nakamura, Jiang He, Min Jin Go, Serge Hercberg, Wendy L. McArdle, Philipp S. Wild, Florian Ernst, Paul Mitchell, Wolfgang Koenig, Caroline S. Fox, S. J.Cathy Fann, Janine F. Felix, Anna F. Dominiczak, Mike A. Nalls, Erik Ingelsson, Mario A. Morken, Susana Eyheramendy, Christopher Newton-Cheh, Igor Rudan, D. G. Vinay, Christopher P. Nelson, Ervin R. Fox, Xiuqing Guo, Jing Hua Zhao, Rick Twee-Hee Ong, Margaret M. Redfield, Oscar H. Franco, Yongmei Liu, Fulvio Ricceri, Mark A. Hlatky, Bernhard Paulweber, Mingyao Li, Themistocles L. Assimes, Karl Winkler, Inês Barroso, Sylvia E. Rosas, M Walker, Richard W Morris, Bo Hedblad, Hakon Hakonarson, Sonny Dandona, Peter H. Whincup, Martin Adam, Vilmundur Gudnason, Daniel Ackermann, Qiong Yang, Cuno S. P. M. Uiterwaal, Paul M. Ridker, George Davey Smith, Li Chen, C. Sinning, Terri L. Young, Jer-Yuarn Wu, Walter Palmas, Will Longstreth, Joe Devaney, Pavel Hamet, Xiaofeng Zhu, Fredrik Nyberg, Wilfried Renner, Anuj Goel, L. Adrienne Cupples, Nish Chaturvedi, Iftikhar J. Kullo, Nicholas D. Hastie, Aude Saint-Pierre, Panos Deloukas, Smita R. Kulkarni, Eric Boerwinkle, Wolfram Goessling, Gian Andri Thun, Eric J.G. Sijbrands, Shih-Jen Hwang, Carole Proust, Hirotsugu Ueshima, Kristian Hveem, Pierre Meneton, Joshua C. Denny, Olivier Devuyst, Kerri L. Wiggins, Ming-Huei Chen, Robert W. Lawrence, Robert L. Wilensky, Andre Franke, Nicole Soranzo, Simon Heath, Margot Haun, Karlhans Endlich, David Altshuler, Harald Grallert, Laurence Tiret, Luigi Ferrucci, Caroline Hayward, Sudha Seshadri, Bénédicte Stengel, Lynne E. Wagenknecht, John Attia, Andreas Ziegler, Renate B. Schnabel, Stefan Schreiber, Santosh Dahgam, Kurt Lohman, Christian M. Shaffer, Barbara Ludwig, Katalin Susztak, Chien-Hsiun Chen, Michele K. Evans, Paolo Vineis, Guo Li, Thomas J. Wang, Meena Kumari, Heather M. Stringham, Bruce M. Psaty, Norman Klopp, Halit Ongen, Ben A. Oostra, Stefan Coassin, Petra Bruse, Wei-Min Chen, Unnur Thorsteinsdottir, Charles N. Rotimi, Robert J. Carroll, Muredach P. Reilly, Niek Verweij, Dena G. Hernandez, Amy J. Swift, Barbara Kollerits, Hyung Lae Kim, Cristian Pattaro, Ivana Kolcic, Ronit Katz, John M. C. Connell, Dan E. Arking, Albert W. Dreisbach, Peter Vollenweider, C. S. Janipalli, Jian'an Luan, Erkki Vartiainen, James T. Willerson, John R. Thompson, Daniela Toniolo, Lyle J. Palmer, Alexander Teumer, Serkalem Demissie-Banjaw, Stella Trompet, James E. Hixson, Sue Shaw-Hawkins, Rossella Sorice, Bernhard R. Winkelmann, John Danesh, Anthony J. Balmforth, Toshio Ogihara, Jyotika K. Fernandes, Ulf Gyllensten, Ville Aalto, Åsa Johansson, Andres Metspalu, John F. Peden, Diana Kuh, Medea Imboden, Antonio Lupo, Su Chi Lim, Young-Jin Kim, Giovanni Malerba, Yurii S. Aulchenko, Satoshi Umemura, Ioanna Tzoulaki, Alan B. Weder, Helena Schmidt, Gerjan Navis, Susan R. Heckbert, Hans J. Rupprecht, Edward G. Lakatta, Christian Gieger, Najaf Amin, Paul Muntner, Lenore J. Launer, Ivana Persico, Hugh Watkins, Ian Ford, K. Radha Mani, Sylvia Stracke, Johanna Kuusisto, John Chalmers, Muhammad Islam, Lars Lind, Stefan R. Bornstein, Marjo-Riitta Järvelin, J. H. Young, Reiner Biffar, Santhi K. Ganesh, Kazuhiko Yamamoto, Annette Peters, Linda S. Adair, Tõnu Esko, Rebecca Hardy, Olga Jarinova, Antonietta Robino, Ruth McPherson, Benjamin F. Voight, Anne U. Jackson, Gang Shi, Stefania Bandinelli, Peter J. van der Most, John S. Gottdiener, Ying A. Wang, Mariza de Andrade, Joshua C. Bis, Leslie J. Raffel, Man Li, Jemma C. Hopewell, Bernhard O. Böhm, Aaron R. Folsom, Noël P. Burtt, S. Sidney, Diana Zelenika, Yuri Milaneschi, Pilar Galan, Iris M. Heid, Bernhard K. Krämer, Jean-Michel Gaspoz, Lynda M. Rose, Massimiliano Cocca, Jaap W. Deckers, Martin Farrall, Kent D. Taylor, Albert V. Smith, Candace Guiducci, Alan R. Shuldiner, Shiro Maeda, Liming Qu, Marilyn C. Cornelis, Xiaoling Wang, Daniel Shriner, Jutta Palmen, Yingchang Lu, Heyo K. Kroemer, Pio D'Adamo, Stephan J. L. Bakker, Tamara B. Harris, Myriam Rheinberger, Tetsuro Miki, Audrey Y. Chu, Ramachandran S. Vasan, Fuu Jen Tsai, Jan A. Staessen, Daniel I. Chasman, Jan Stritzke, Jasmin Divers, Meredith C. Foster, Jeanette M. Stafford, Maksim Struchalin, Arne Schillert, Jacques S. Beckmann, Mark E. Cooper, Jean-Charles Lambert, Mario Pirastu, Katja Butterbach, Carl G. P. Platou, Yan V. Sun, Marcus Fischer, Maciej Tomaszewski, Karl Werdan, Peng Chen, Daniel J. Rader, Thomas Münzel, Lowell F. Satler, Tom R. Gaunt, Brenda W.J.H. Penninx, William H. Matthai, John Whitfield, Rita P.S. Middelberg, Margus Viigimaa, Toshihiro Tanaka, Ida Yii Der Chen, Morris J. Brown, Valur Emilsson, J. Viikari, Wolfgang Lieb, Stephen E. Epstein, Harald Dobnig, Aravinda Chakravarti, Patrick Linsel-Nitschke, Stefan Pilz, Angela Doering, Sarah H. Wild, Patricia B. Munroe, Megan E. Rudock, Nicole Probst-Hensch, Danish Saleheen, Diederick E. Grobbee, Anke Tönjes, Narisu Narisu, Annika Rosengren, Masato Isono, Catherine Helmer, M. J.Kranthi Kumar, Alanna C. Morrison, Kay-Tee Khaw, Tanja Zeller, Jeffrey R. O'Connell, Christian Müller, Georg Homuth, Giriraj R. Chandak, Pankaj Sharma, Marcus Dörr, Veikko Salomaa, Paul F. O'Reilly, David Hadley, Hermann Brenner, Paolo Gasparini, Nanette R. Lee, Bamidele O. Tayo, Robert Clarke, Henri Wallaschofski, Marketa Sjögren, Abbas Dehghan, Melanie Waldenberger, Neil Risch, Vasyl Pihur, Jessica D. Faul, François Cambien, Christian Fuchsberger, Nicholas G. Martin, John C. Chambers, Zouhair Aherrahrou, Karl J. Lackner, Leif Groop, Matthias Olden, Wiek H. van Gilst, Mathias Gorski, Yvonne T. van der Schouw, Patrick Diemert, Christoph Bickel, Yik Ying Teo, Giorgio Pistis, Ruth J. F. Loos, Gudrun Veldre, Thorsten Reffelmann, Lude Franke, Karen L. Mohlke, Stefan Blankenberg, Massimo Mangino, Ian N. M. Day, Atsushi Takahashi, Alan B. Zonderman, Hua Tang, Reijo Laaksonen, Holly Kramer, Gary C. Curhan, Adrienne Tin, Talin Haritunians, Loic Yengo, Philip Howard, Arnika Kathleen Wagner, Anna Maria Corsi, Yen Pei C. Chang, Karin Halina Greiser, Jeanette Erdmann, Solveig Gretarsdottir, Sanjay Kinra, Alex Parker, Belen Ponte, Marina Ciullo, Michael Preuss, Tin Aung, Nicholas L. Smith, Michiaki Kubo, Richard N. Bergman, Alan S. Go, Patricia P. Chang, Gudmundur Thorgeirsson, Christa Meisinger, Gonçalo R. Abecasis, Maria Blettner, Jaana Laitinen, Daniel Taliun, Carlos Iribarren, Paavo Zitting, Thomas Lumley, Andreas Meinitzer, Wayne D. Rosamond, Daehee Kang, Johanne Tremblay, Stephan B. Felix, Colin A. McKenzie, Yuan-Tsong Chen, Lyudmyla Kedenko, Mladen Boban, Fadi J. Charchar, Adebowale Adeyemo, Brendan M. Buckley, Jennifer A. Smith, Reinhold Schmidt, Jaspal S. Kooner, Gavin Lucas, Paul Elliott, Dorairajan Prabhakaran, Tune H. Pers, Tunde Salako, Terrence Forrester, Paul Burton, Jeffrey R. Gulcher, Kelly A. Volcik, Richard M. Myers, Andreas Tomaschitz, H.-Erich Wichmann, Jie Yao, Giuseppe Matullo, Carsten A. Böger, Henry Völzke, Daniela Ruggiero, Federico Murgia, Yoshikuni Kita, Augustine Kong, Giovanni Gambaro, Cinzia Sala, Peter P. Pramstaller, James Scott, Maris Laan, Laura J. Scott, Alistair S. Hall, Sanaz Sedaghat, James F. Wilson, Joanne M. Murabito, Yi-An Ko, Honghuang Lin, Mark Seielstad, Leena Peltonen, Sven Bergmann, Thomas Meitinger, Matthias Nauck, María Soler Artigas, Thomas Illig, Nanette I. Steinle, Samer S. Najjar, Christina Loley, Debbie A Lawlor, Steven C. Hunt, Yali Li, Weihua Zhang, Jie Jin Wang, Daniele Cusi, Marco Orrù, Stephen P. Fortmann, Melissa Garcia, Barry I. Freedman, Joseph M. Lindsay, Juan P. Casas, Tomohiro Katsuya, Grant W. Montgomery, Hubert Scharnagl, Khanh-Dung H. Nguyen, Steven M. Schwartz, Afshin Parsa, Elizabeth G. Holliday, Murielle Bochud, Kiran Musunuru, Bruno H. Stricker, Lori L. Bonnycastle, Ilja M. Nolte, Timothy M. Frayling, Stefan Enroth, Michiel L. Bots, Mark J. Caulfield, Laura Portas, Vincent Chouraki, Carl D. Langefeld, Eran Halperin, Shufeng Chen, Philippa J. Talmud, Terho Lehtimäki, Steve E. Humphries, Gudmar Thorleifsson, Anika Grosshennig, Norbert Watzinger, Fumihiko Takeuchi, Pim van der Harst, Takayoshi Ohkubo, Nabila Bouatia-Naji, Erwin P. Bottinger, Roberto Elosua, Andrew Wong, Vladan Mijatovic, Maija K. Garnaas, Robert Zweiker, Joel N. Hirschhorn, Winfried März, Nilesh J. Samani, Inke R. König, Frank B. Hu, Marcus E. Kleber, Francis S. Collins, Elena Rochtchina, Ewa Zukowska-Szczechowska, Yong Li, Ayse Demirkan, Gina Hilton, G. Ehret, Thomas H. Mosley, Markus Perola, Alexandre F.R. Stewart, Josef Coresh, Olli T. Raitakari, Feng Zhang, Mark Lathrop, Michael Marmot, Yanbin Dong, Christopher J. O'Donnell, Kristin D. Marciante, Asif Rasheed, Mary F. Feitosa, Mary Susan Burnett, Rory Collins, J. Wouter Jukema, Nele Friedrich, Aida Karina Dieffenbach, Ying Wu, Yoon Shin Cho, Aaron Isaacs, Haidong Zhu, Marie Metzger, Myriam Alexander, Tanja B. Grammer, Tatiana Kuznetsova, Dabeeru C. Rao, Jayashri Aragam, Augusto D. Pichard, Jaakko Tuomilehto, Louise V. Wain, Elizabeth J. Atkinson, Tim D. Spector, Reedik Mägi, Tiit Nikopensius, Kenneth M. Kent, Guangju Zhai, Andrew D. Johnson, Menno Pruijm, David P. Strachan, Martin D. Tobin, Joban Sehmi, Janja Nahrstedt, E. Shyong Tai, Thor Aspelund, Jürgen Grässler, Hilma Holm, Matthew Denniff, Joshua W. Knowles, Tien Yin Wong, Erika Salvi, James F. Meschia, Dongfeng Gu, Ron Waksman, Stacey Gabriel, Judith A. Hoffman Bolton, Michael Boehnke, Johannes Haerting, Darina Czamara, Heribert Schunkert, Thomas Quertermous, Peter M. Nilsson, Jong-Young Lee, Yasuharu Tabara, Chittaranjan S. Yajnik, Daniel Levy, John Beilby, Fernando Rivadeneira, Claire Perret, Gudny Eiriksdottir, Jingzhong Ding, George A. Wells, Harold Snieder, Ayo P. Doumatey, Dag S. Thelle, Anja Medack, N. Charlotte Onland-Moret, Michael Stumvoll, David Ellinghaus, Ingrid B. Borecki, Tatsuhiko Tsunoda, Ian H. de Boer, M. Arfan Ikram, Andrew M. Taylor, Johannes H. Smit, Gary F. Mitchell, Anna-Liisa Hartikainen, Markku Laakso, Mark McEvoy, Andrew S. Plump, Toby Johnson, Cornelia M. van Duijn, Ozren Polasek, Wilmar Igl, Vincent Mooser, Rodney J. Scott, Mika Kähönen, Peter Schwarz, Psychiatry, EMGO - Mental health, Pattaro, Cristian, Teumer, Alexander, Gorski, Mathia, Chu, Audrey Y., Li, Man, Mijatovic, Vladan, Garnaas, Maija, Tin, Adrienne, Sorice, Rossella, Li, Yong, Taliun, Daniel, Olden, Matthia, Foster, Meredith, Yang, Qiong, Chen, Ming Huei, Pers, Tune H., Johnson, Andrew D., Ko, Yi An, Fuchsberger, Christian, Tayo, Bamidele, Nalls, Michael, Feitosa, Mary F., Isaacs, Aaron, Dehghan, Abba, D'Adamo, ADAMO PIO, Adeyemo, Adebowale, Dieffenbach, Aida Karina, Zonderman, Alan B., Nolte, Ilja M., Van Der Most, Peter J., Wright, Alan F., Shuldiner, Alan R., Morrison, Alanna C., Hofman, Albert, Smith, Albert V., Dreisbach, Albert W., Franke, Andre, Uitterlinden, Andre G., Metspalu, Andre, Tonjes, Anke, Lupo, Antonio, Robino, Antonietta, Johansson, Åsa, Demirkan, Ayse, Kollerits, Barbara, Freedman, Barry I., Ponte, Belen, Oostra, Ben A., Paulweber, Bernhard, Krämer, Bernhard K., Mitchell, Braxton D., Buckley, Brendan M., Peralta, Carmen A., Hayward, Caroline, Helmer, Catherine, Rotimi, Charles N., Shaffer, Christian M., Müller, Christian, Sala, Cinzia, Van Duijn, Cornelia M., Saint Pierre, Aude, Ackermann, Daniel, Shriner, Daniel, Ruggiero, Daniela, Toniolo, Daniela, Lu, Yingchang, Cusi, Daniele, Czamara, Darina, Ellinghaus, David, Siscovick, David S., Ruderfer, Dougla, Gieger, Christian, Grallert, Harald, Rochtchina, Elena, Atkinson, Elizabeth J., Holliday, Elizabeth G., Boerwinkle, Eric, Salvi, Erika, Bottinger, Erwin P., Murgia, Federico, Rivadeneira, Fernando, Ernst, Florian, Kronenberg, Florian, Hu, Frank B., Navis, Gerjan J., Curhan, Gary C., Ehret, George B., Homuth, Georg, Coassin, Stefan, Thun, Gian Andri, Pistis, Giorgio, Gambaro, Giovanni, Malerba, Giovanni, Montgomery, Grant W., Eiriksdottir, Gudny, Jacobs, Gunnar, Li, Guo, Wichmann, H. Erich, Campbell, Harry, Schmidt, Helena, Wallaschofski, Henri, Völzke, Henry, Brenner, Hermann, Kroemer, Heyo K., Kramer, Holly, Lin, Honghuang, Leach, I. Mateo, Ford, Ian, Guessous, Idri, Rudan, Igor, Prokopenko, Inga, Borecki, Ingrid, Heid, Iris M., Kolcic, Ivana, Persico, Ivana, Jukema, J. 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L., Bandinelli, Stefania, Barroso, Ine, Beckmann, Jacques S., Beilby, John P., Bergman, Richard N., Bergmann, Sven, Bis, Joshua C., Boehnke, Michael, Bonnycastle, Lori L., Bornstein, Stefan R., Bots, Michiel L., Bragg Gresham, Jennifer L., Brand, Stefan Martin, Brand, Eva, Braund, Peter S., Brown, Morris J., Burton, Paul R., Casas, Juan P., Caulfield, Mark J., Chakravarti, Aravinda, Chambers, John C., Chandak, Giriraj R., Chang, Yen Pei C., Charchar, Fadi J., Chaturvedi, Nish, Cho, Yoon Shin, Clarke, Robert, Collins, Francis S., Collins, Rory, Connell, John M., Cooper, Jackie A., Cooper, Matthew N., Cooper, Richard S., Corsi, Anna Maria, Dörr, Marcu, Dahgam, Santosh, Danesh, John, Smith, George Davey, Day, Ian N. M., Deloukas, Pano, Denniff, Matthew, Dominiczak, Anna F., Dong, Yanbin, Doumatey, Ayo, Elliott, Paul, Elosua, Roberto, Erdmann, Jeanette, Eyheramendy, Susana, Farrall, Martin, Fava, Cristiano, Forrester, Terrence, Fowkes, F. Gerald R., Fox, Ervin R., Frayling, Timothy M., Galan, Pilar, Ganesh, Santhi K., Garcia, Melissa, Gaunt, Tom R., Glazer, Nicole L., Go, Min Jin, Goel, Anuj, Grässler, Jürgen, Grobbee, Diederick E., Groop, Leif, Guarrera, Simonetta, Guo, Xiuqing, Hadley, David, Hamsten, Ander, Han, Bok Ghee, Hardy, Rebecca, Hartikainen, Anna Liisa, Heath, Simon, Heckbert, Susan R., Hedblad, Bo, Hercberg, Serge, Hernandez, Dena, Hicks, Andrew A., Hilton, Gina, Hingorani, Aroon D., Hoffman Bolton, Judith A., Hopewell, Jemma C., Howard, Philip, Humphries, Steve E., Hunt, Steven C., Hveem, Kristian, Ikram, M. Arfan, Islam, Muhammad, Iwai, Naoharu, Jarvelin, Marjo Riitta, Jackson, Anne U., Jafar, Tazeen H., Janipalli, Charles S., Johnson, Toby, Kathiresan, Sekar, Khaw, Kay Tee, Kim, Hyung Lae, Kinra, Sanjay, Kita, Yoshikuni, Kivimaki, Mika, Kooner, Jaspal S., Kumar, M. J. Kranthi, Kuh, Diana, Kulkarni, Smita R., Kumari, Meena, Kuusisto, Johanna, Kuznetsova, Tatiana, Laakso, Markku, Laan, Mari, Laitinen, Jaana, Lakatta, Edward G., Langefeld, Carl D., Larson, Martin G., Lathrop, Mark, Lawlor, Debbie A., Lawrence, Robert W., Lee, Jong Young, Lee, Nanette R., Levy, Daniel, Li, Yali, Longstreth, Will T., Luan, Jian'An, Lucas, Gavin, Ludwig, Barbara, Mangino, Massimo, Mani, K. Radha, Marmot, Michael G., Mattace Raso, Francesco U. S., Matullo, Giuseppe, Mcardle, Wendy L., Mckenzie, Colin A., Meitinger, Thoma, Melander, Olle, Meneton, Pierre, Meschia, James F., Miki, Tetsuro, Milaneschi, Yuri, Mohlke, Karen L., Mooser, Vincent, Morken, Mario A., Morris, Richard W., Mosley, Thomas H., Najjar, Samer, Narisu, Narisu, Newton Cheh, Christopher, Nguyen, Khanh Dung Hoang, Nilsson, Peter, Nyberg, Fredrik, O'Donnell, Christopher J., Ogihara, Toshio, Ohkubo, Takayoshi, Okamura, Tomonori, Ong, Rick Twee Hee, Ongen, Halit, Onland Moret, N. Charlotte, O'Reilly, Paul F., Org, Elin, Orru, Marco, Palmas, Walter, Palmen, Jutta, Palmer, Lyle J., Palmer, Nicholette D., Parker, Alex N., Peden, John F., Peltonen, Leena, Perola, Marku, Pihur, Vasyl, Platou, Carl G. P., Plump, Andrew, Prabhakaran, Dorairajan, Psaty, Bruce M., Raffel, Leslie J., Rao, Dabeeru C., Rasheed, Asif, Ricceri, Fulvio, Rice, Kenneth M., Rosengren, Annika, Rotter, Jerome I., Rudock, Megan E., Sõber, Siim, Salako, Tunde, Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Schwartz, Steven M., Schwarz, Peter E. H., Scott, Laura J., Scott, Jame, Scuteri, Angelo, Sehmi, Joban S., Seielstad, Mark, Seshadri, Sudha, Sharma, Pankaj, Shaw Hawkins, Sue, Shi, Gang, Shrine, Nick R. G., Sijbrands, Eric J. G., Sim, Xueling, Singleton, Andrew, Sjögren, Marketa, Smith, Nicholas L., Artigas, Maria Soler, Spector, Tim D., Staessen, Jan A., Stancakova, Alena, Steinle, Nanette I., Strachan, David P., Stringham, Heather M., Sun, Yan V., Swift, Amy J., Tabara, Yasuharu, Tai, E. Shyong, Talmud, Philippa J., Taylor, Andrew, Terzic, Jano, Thelle, Dag S., Tobin, Martin D., Tomaszewski, Maciej, Tripathy, Vikal, Tuomilehto, Jaakko, Tzoulaki, Ioanna, Uda, Manuela, Ueshima, Hirotsugu, Uiterwaal, Cuno S. P. M., Umemura, Satoshi, Van Der Harst, Pim, Van Der Schouw, Yvonne T., Van Gilst, Wiek H., Vartiainen, Erkki, Vasan, Ramachandran S., Veldre, Gudrun, Verwoert, Germaine C., Viigimaa, Margu, Vinay, D. G., Vineis, Paolo, Voight, Benjamin F., Vollenweider, Peter, Wagenknecht, Lynne E., Wain, Louise V., Wang, Xiaoling, Wang, Thomas J., Wareham, Nicholas J., Watkins, Hugh, Weder, Alan B., Whincup, Peter H., Wiggins, Kerri L., Witteman, Jacqueline C. M., Wong, Andrew, Wu, Ying, Yajnik, Chittaranjan S., Yao, Jie, Young, J. H., Zelenika, Diana, Zhai, Guangju, Zhang, Weihua, Zhang, Feng, Zhao, Jing Hua, Zhu, Haidong, Zhu, Xiaofeng, Zitting, Paavo, Zukowska Szczechowska, Ewa, Okada, Yukinori, Wu, Jer Yuarn, Gu, Dongfeng, Takeuchi, Fumihiko, Takahashi, Atsushi, Maeda, Shiro, Tsunoda, Tatsuhiko, Chen, Peng, Lim, Su Chi, Wong, Tien Yin, Liu, Jianjun, Young, Terri L., Aung, Tin, Teo, Yik Ying, Kim, Young Jin, Kang, Daehee, Chen, Chien Hsiun, Tsai, Fuu Jen, Chang, Li Ching, Fann, S. J. Cathy, Mei, Hao, Hixson, James E., Chen, Shufeng, Katsuya, Tomohiro, Isono, Masato, Albrecht, Eva, Yamamoto, Kazuhiko, Kubo, Michiaki, Nakamura, Yusuke, Kamatani, Naoyuki, Kato, Norihiro, He, Jiang, Chen, Yuan Tsong, Tanaka, Toshihiro, Reilly, Muredach P., Schunkert, Heribert, Assimes, Themistocles L., Hall, Alistair, Hengstenberg, Christian, König, Inke R., Laaksonen, Reijo, Mcpherson, Ruth, Thompson, John R., Thorsteinsdottir, Unnur, Ziegler, Andrea, Absher, Devin, Chen, Li, Cupples, L. 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R., Fortmann, Stephen, Go, Alan, Hlatky, Mark, Iribarren, Carlo, Knowles, Joshua, Myers, Richard, Quertermous, Thoma, Sidney, Steven, Risch, Neil, Tang, Hua, Blankenberg, Stefan, Schnabel, Renate, Sinning, Christoph, Lackner, Karl J., Tiret, Laurence, Nicaud, Viviane, Cambien, Francoi, Bickel, Christoph, Rupprecht, Hans J., Perret, Claire, Proust, Carole, Münzel, Thomas F., Barbalic, Maja, Chen, Ida Yii Der, Demissie Banjaw, Serkalem, Folsom, Aaron, Lumley, Thoma, Marciante, Kristin, Taylor, Kent D., Volcik, Kelly, Gretarsdottir, Solveig, Gulcher, Jeffrey R., Kong, Augustine, Stefansson, Kari, Thorgeirsson, Gudmundur, Andersen, Karl, Fischer, Marcu, Grosshennig, Anika, Linsel Nitschke, Patrick, Stark, Klau, Schreiber, Stefan, Aherrahrou, Zouhair, Bruse, Petra, Doering, Angela, Klopp, Norman, Diemert, Patrick, Loley, Christina, Medack, Anja, Nahrstedt, Janja, Peters, Annette, Wagner, Arnika K., Willenborg, Christina, Böhm, Bernhard O., Dobnig, Harald, Grammer, Tanja B., Hoffmann, Michael M., Meinitzer, Andrea, Winkelmann, Bernhard R., Pilz, Stefan, Renner, Wilfried, Scharnagl, Hubert, Stojakovic, Tatjana, Tomaschitz, Andrea, Winkler, Karl, Guiducci, Candace, Burtt, Noel, Gabriel, Stacey B., Dandona, Sonny, Jarinova, Olga, Qu, Liming, Wilensky, Robert, Matthai, William, Hakonarson, Hakon H., Devaney, Joe, Burnett, Mary Susan, Pichard, Augusto D., Kent, Kenneth M., Satler, Lowell, Lindsay, Joseph M., Waksman, Ron, Knouff, Christopher W., Waterworth, Dawn M., Walker, Max C., Epstein, Stephen E., Rader, Daniel J., Nelson, Christopher P., Wright, Benjamin J., Balmforth, Anthony J., Ball, Stephen G., Loehr, Laura R., Rosamond, Wayne D., Benjamin, Emelia, Haritunians, Talin, Couper, David, Murabito, Joanne, Wang, Ying A., Stricker, Bruno H., Chang, Patricia P., Willerson, James T., Felix, Stephan B., Watzinger, Norbert, Aragam, Jayashri, Zweiker, Robert, Lind, Lar, Rodeheffer, Richard J., Greiser, Karin Halina, Deckers, Jaap W., Stritzke, Jan, Ingelsson, Erik, Kullo, Iftikhar, Haerting, Johanne, Reffelmann, Thorsten, Redfield, Margaret M., Werdan, Karl, Mitchell, Gary F., Arnett, Donna K., Gottdiener, John S., Blettner, Maria, Friedrich, Nele, Kovacs, Peter, Wild, Philipp S., Froguel, Philippe, Rettig, Rainer, Mägi, Reedik, Biffar, Reiner, Schmidt, Reinhold, Middelberg, Rita P. S., Carroll, Robert J., Penninx, Brenda W., Scott, Rodney J., Katz, Ronit, Sedaghat, Sanaz, Wild, Sarah H., Kardia, Sharon L. R., Ulivi, Sheila, Hwang, Shih Jen, Enroth, Stefan, Kloiber, Stefan, Trompet, Stella, Stengel, Benedicte, Hancock, Stephen J., Turner, Stephen T., Rosas, Sylvia E., Stracke, Sylvia, Harris, Tamara B., Zeller, Tanja, Zemunik, Tatijana, Lehtimäki, Terho, Illig, Thoma, Aspelund, Thor, Nikopensius, Tiit, Esko, Tonu, Tanaka, Toshiko, Gyllensten, Ulf, Völker, Uwe, Emilsson, Valur, Vitart, Veronique, Aalto, Ville, Gudnason, Vilmundur, Chouraki, Vincent, Chen, Wei Min, Igl, Wilmar, März, Winfried, Koenig, Wolfgang, Lieb, Wolfgang, Loos, Ruth J. F., Liu, Yongmei, Snieder, Harold, Pramstaller, Peter P., Parsa, Afshin, O'Connell, Jeffrey R., Susztak, Katalin, Hamet, Pavel, Tremblay, Johanne, De Boer, Ian H., Böger, Carsten A., Goessling, Wolfram, Chasman, Daniel I., Köttgen, Anna, Kao, W. H. Linda, Fox, Caroline S., RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, Biochemie, RS: FHML MaCSBio, Ehret, Georg Benedikt, Guessous, Idris, Gaspoz, Jean-Michel, Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Polymer Chemistry and Bioengineering, Value, Affordability and Sustainability (VALUE), Stem Cell Aging Leukemia and Lymphoma (SALL), Epidemiology, Public Health, Internal Medicine, Clinical Genetics, Erasmus MC other, Genetic Identification, ICBP Consortium, AGEN Consortium, CHARGe-Heart Failure Group, ECHOGen Consortium, CARDIOGRAM, Abecasis, GR., Adair, LS., Alexander, M., Altshuler, D., Amin, N., Arking, DE., Arora, P., Aulchenko, Y., Bakker, SJ., Bandinelli, S., Barroso, I., Beckmann, JS., Beilby, JP., Bergman, RN., Bergmann, S., Bis, JC., Boehnke, M., Bonnycastle, LL., Bornstein, SR., Bots, ML., Bragg-Gresham, JL., Brand, SM., Brand, E., Braund, PS., Brown, MJ., Burton, PR., Casas, JP., Caulfield, MJ., Chakravarti, A., Chambers, JC., Chandak, GR., Chang, YP., Charchar, FJ., Chaturvedi, N., Shin Cho, Y., Clarke, R., Collins, FS., Collins, R., Connell, JM., Cooper, JA., Cooper, MN., Cooper, RS., Corsi, AM., Dörr, M., Dahgam, S., Danesh, J., Davey Smith, G., Day, IN., Deloukas, P., Denniff, M., Dominiczak, AF., Dong, Y., Doumatey, A., Elliott, P., Elosua, R., Erdmann, J., Eyheramendy, S., Farrall, M., Fava, C., Forrester, T., Fowkes, FG., Fox, ER., Frayling, TM., Galan, P., Ganesh, SK., Garcia, M., Gaunt, TR., Glazer, NL., Go, MJ., Goel, A., Grässler, J., Grobbee, DE., Groop, L., Guarrera, S., Guo, X., Hadley, D., Hamsten, A., Han, BG., Hardy, R., Hartikainen, AL., Heath, S., Heckbert, SR., Hedblad, B., Hercberg, S., Hernandez, D., Hicks, AA., Hilton, G., Hingorani, AD., Bolton, JA., Hopewell, JC., Howard, P., Humphries, SE., Hunt, SC., Hveem, K., Ikram, MA., Islam, M., Iwai, N., Jarvelin, MR., Jackson, AU., Jafar, TH., Janipalli, CS., Johnson, T., Kathiresan, S., Khaw, KT., Kim, HL., Kinra, S., Kita, Y., Kivimaki, M., Kooner, JS., Kumar, MJ., Kuh, D., Kulkarni, SR., Kumari, M., Kuusisto, J., Kuznetsova, T., Laakso, M., Laan, M., Laitinen, J., Lakatta, EG., Langefeld, CD., Larson, MG., Lathrop, M., Lawlor, DA., Lawrence, RW., Lee, JY., Lee, NR., Levy, D., Li, Y., Longstreth, WT., Luan£££Jian'an£££ J., Lucas, G., Ludwig, B., Mangino, M., Mani, KR., Marmot, MG., Mattace-Raso, FU., Matullo, G., McArdle, WL., McKenzie, CA., Meitinger, T., Melander, O., Meneton, P., Meschia, JF., Miki, T., Milaneschi, Y., Mohlke, KL., Mooser, V., Morken, MA., Morris, RW., Mosley, TH., Najjar, S., Narisu, N., Newton-Cheh, C., Nguyen, KD., Nilsson, P., Nyberg, F., O'Donnell, CJ., Ogihara, T., Ohkubo, T., Okamura, T., Ong, RT., Ongen, H., Onland-Moret, NC., O'Reilly, PF., Org, E., Orru, M., Palmas, W., Palmen, J., Palmer, LJ., Palmer, ND., Parker, AN., Peden, JF., Peltonen, L., Perola, M., Pihur, V., Platou, CG., Plump, A., Prabhakaran, D., Psaty, BM., Raffel, LJ., Rao, DC., Rasheed, A., Ricceri, F., Rice, KM., Rosengren, A., Rotter, JI., Rudock, ME., Sõber, S., Salako, T., Saleheen, D., Salomaa, V., Samani, NJ., Schwartz, SM., Schwarz, PE., Scott, LJ., Scott, J., Scuteri, A., Sehmi, JS., Seielstad, M., Seshadri, S., Sharma, P., Shaw-Hawkins, S., Shi, G., Shrine, NR., Sijbrands, EJ., Sim, X., Singleton, A., Sjögren, M., Smith, NL., Soler Artigas, M., Spector, TD., Staessen, JA., Stancakova, A., Steinle, NI., Strachan, DP., Stringham, HM., Sun, YV., Swift, AJ., Tabara, Y., Tai, ES., Talmud, PJ., Taylor, A., Terzic, J., Thelle, DS., Tobin, MD., Tomaszewski, M., Tripathy, V., Tuomilehto, J., Tzoulaki, I., Uda, M., Ueshima, H., Uiterwaal, CS., Umemura, S., van der Harst, P., van der Schouw YT., van Gilst WH., Vartiainen, E., Vasan, RS., Veldre, G., Verwoert, GC., Viigimaa, M., Vinay, DG., Vineis, P., Voight, BF., Vollenweider, P., Wagenknecht, LE., Wain, LV., Wang, X., Wang, TJ., Wareham, NJ., Watkins, H., Weder, AB., Whincup, PH., Wiggins, KL., Witteman, JC., Wong, A., Wu, Y., Yajnik, CS., Yao, J., Young, JH., Zelenika, D., Zhai, G., Zhang, W., Zhang, F., Zhao, JH., Zhu, H., Zhu, X., Zitting, P., Zukowska-Szczechowska, E., Okada, Y., Wu, JY., Gu, D., Takeuchi, F., Takahashi, A., Maeda, S., Tsunoda, T., Chen, P., Lim, SC., Wong, TY., Liu, J., Young, TL., Aung, T., Teo, YY., Kim, YJ., Kang, D., Chen, CH., Tsai, FJ., Chang, LC., Fann, SJ., Mei, H., Hixson, JE., Chen, S., Katsuya, T., Isono, M., Albrecht, E., Yamamoto, K., Kubo, M., Nakamura, Y., Kamatani, N., Kato, N., He, J., Chen, YT., Tanaka, T., Reilly, MP., Schunkert, H., Assimes, TL., Hall, A., Hengstenberg, C., König, IR., Laaksonen, R., McPherson, R., Thompson, JR., Thorsteinsdottir, U., Ziegler, A., Absher, D., Chen, L., Cupples, LA., Halperin, E., Li, M., Musunuru, K., Preuss, M., Schillert, A., Thorleifsson, G., Wells, GA., Holm, H., Roberts, R., Stewart, AF., Fortmann, S., Go, A., Hlatky, M., Iribarren, C., Knowles, J., Myers, R., Quertermous, T., Sidney, S., Risch, N., Tang, H., Blankenberg, S., Schnabel, R., Sinning, C., Lackner, KJ., Tiret, L., Nicaud, V., Cambien, F., Bickel, C., Rupprecht, HJ., Perret, C., Proust, C., Münzel, TF., Barbalic, M., Chen, IY., Demissie-Banjaw, S., Folsom, A., Lumley, T., Marciante, K., Taylor, KD., Volcik, K., Gretarsdottir, S., Gulcher, JR., Kong, A., Stefansson, K., Thorgeirsson, G., Andersen, K., Fischer, M., Grosshennig, A., Linsel-Nitschke, P., Stark, K., Schreiber, S., Aherrahrou, Z., Bruse, P., Doering, A., Klopp, N., Diemert, P., Loley, C., Medack, A., Nahrstedt, J., Peters, A., Wagner, AK., Willenborg, C., Böhm, BO., Dobnig, H., Grammer, TB., Hoffmann, MM., Meinitzer, A., Winkelmann, BR., Pilz, S., Renner, W., Scharnagl, H., Stojakovic, T., Tomaschitz, A., Winkler, K., Guiducci, C., Burtt, N., Gabriel, SB., Dandona, S., Jarinova, O., Qu, L., Wilensky, R., Matthai, W., Hakonarson, HH., Devaney, J., Burnett, MS., Pichard, AD., Kent, KM., Satler, L., Lindsay, JM., Waksman, R., Knouff, CW., Waterworth, DM., Walker, MC., Epstein, SE., Rader, DJ., Nelson, CP., Wright, BJ., Balmforth, AJ., Ball, SG., Loehr, LR., Rosamond, WD., Benjamin, E., Haritunians, T., Couper, D., Murabito, J., Wang, YA., Stricker, BH., Chang, PP., Willerson, JT., Felix, SB., Watzinger, N., Aragam, J., Zweiker, R., Lind, L., Rodeheffer, RJ., Greiser, KH., Deckers, JW., Stritzke, J., Ingelsson, E., Kullo, I., Haerting, J., Reffelmann, T., Redfield, MM., Werdan, K., Mitchell, GF., Arnett, DK., Gottdiener, JS., Blettner, M., and Friedrich, N.

Subjects
0301 basic medicine, Nephrology, Genetics and Molecular Biology (all), estimated glomerular filtration rate, estimated glomerular filtration rate, chronic kidney disease, genetic determinants, General Physics and Astronomy, Kidney development, Genome-wide association study, Biochemistry, Settore MED/14 - NEFROLOGIA, Renal Insufficiency, Chronic, Genetics, AGEN Consortium, ddc:616, education.field_of_study, Kidney, Stage renal-disease, Multidisciplinary, Genome-wide association, CHARGe-Heart Failure Group, Gene Expression Regulation, Genome-Wide Association Study, Genotype, Humans, Renal Insufficiency, Chronic, Genetic Predisposition to Disease, Biochemistry, Genetics and Molecular Biology (all), Chemistry (all), Physics and Astronomy (all), Metaanalysis, Renal Insufficiency, Chronic/genetics, Biological sciences, Serum creatinine, medicine.anatomical_structure, Efficient, Ronyons -- Fisiologia, Hypertension, ICBP Consortium, Transmembrane transporter activity, genetic association, loci, kidney function, CARDIOGRAM, Human, medicine.medical_specialty, Science, Population, Renal function, ECHOGen Consortium, Replication, Biology, Environment, Research Support, General Biochemistry, Genetics and Molecular Biology, N.I.H, genetic determinants, 03 medical and health sciences, GENOME-WIDE ASSOCIATION, FALSE DISCOVERY RATES, STAGE RENAL-DISEASE, SERUM CREATININE, METAANALYSIS, VARIANTS, INDIVIDUALS, POPULATION, RISK, HYPERTENSION, Kidney function, Research Support, N.I.H., Extramural, Internal medicine, MD Multidisciplinary, medicine, Journal Article, eGFRcrea, eGFRcys, ddc:610, Genetik, Mortality, education, ddc:613, urogenital system, Individuals, Extramural, General Chemistry, ta3121, medicine.disease, R1, 030104 developmental biology, 570 Life sciences, biology, Genètica, chronic kidney disease, Kidney disease, Meta-Analysis
Abstract

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. J.T. and P.H. are consultants for Servier. J.C. received research grants and honoraria from Servier. K.S. obtained research support from Boehringer Ingelheim. The remaining authors declared no competing financial interests.

Published
2016

31. Epilogue: What the Future Holds: Genomic Medicine at the Heart of Diabetes Management

Author

Michael Boehnke, David Altshuler, and Mark I. McCarthy

Subjects
business.industry, Physiology, Genomics, Genome-wide association study, Computational biology, Environmental exposure, Disease, Type 2 diabetes, medicine.disease, Genetic architecture, Human genetics, Diabetes management, Medicine, business
Abstract

Individual predisposition to type 2 diabetes is influenced by the combination of genetic variants, environmental exposures, behaviour and chance. Human genetics offers a method to identify specific genetic variants that influence disease risk and thereby the pathways and mechanisms through which they operate. These pathways provide a powerful lens through which to develop biological insights into metabolism and disease and have the potential to inform diagnosis and treatment. Indeed, this potential is already being realised in precision medical management of monogenic and syndromic forms of diabetes. While substantial progress has been made identifying genetic variants for the common, multifactorial forms of type 2 diabetes, major challenges remain before we gain insight and translational benefit. The difficulty derives from the genetic architecture of type 2 diabetes and other common diseases, which involves a large number of variants of modest effect, many non-coding and presumably regulatory in nature. The ability to define more complete individual inventories of genetic risk and environmental exposure is only a start towards understanding the complex molecular pathophysiology that underlies disease, understanding that will support the development of integrative readouts that track causal pathogenetic mechanisms and the invention of new therapies that restore homeostasis through these pathways.

Published
2016

32. Burden of Rare Sarcomere Gene Variants in the Framingham and Jackson Heart Study Cohorts

Author

Sekar Kathiresan, James G. Wilson, Jonathan G. Seidman, Heidi L. Rehm, Ramachandran S. Vasan, Jayashri Aragam, Michael Parfenov, Joel N. Hirschhorn, Susan Cheng, Ervin R. Fox, Birgit Funke, Christine E. Seidman, Steven R. DePalma, Daniel S. Herman, Jason Flannick, Christopher J. O'Donnell, Stacey Gabriel, Kaoru Ito, Christopher Newton-Cheh, Emelia J. Benjamin, Namrata Gupta, Alexander G. Bick, David Altshuler, and Herman A. Taylor

Subjects
Adult, Cardiomyopathy, Dilated, Male, Sarcomeres, medicine.medical_specialty, Population, Cardiomyopathy, 030204 cardiovascular system & hematology, Biology, Sarcomere, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Framingham Heart Study, Risk Factors, Report, Internal medicine, Genetics, medicine, Humans, Genetics(clinical), education, Genetics (clinical), Aged, 030304 developmental biology, Aged, 80 and over, 0303 health sciences, education.field_of_study, Framingham Risk Score, Models, Cardiovascular, Hypertrophic cardiomyopathy, Genetic Variation, Cardiomyopathy, Hypertrophic, Middle Aged, medicine.disease, 3. Good health, Cardiovascular Diseases, Cohort, Cardiology, Female, Cohort study
Abstract

Rare sarcomere protein variants cause dominant hypertrophic and dilated cardiomyopathies. To evaluate whether allelic variants in eight sarcomere genes are associated with cardiac morphology and function in the community, we sequenced 3,600 individuals from the Framingham Heart Study (FHS) and Jackson Heart Study (JHS) cohorts. Out of the total, 11.2% of individuals had one or more rare nonsynonymous sarcomere variants. The prevalence of likely pathogenic sarcomere variants was 0.6%, twice the previous estimates; however, only four of the 22 individuals had clinical manifestations of hypertrophic cardiomyopathy. Rare sarcomere variants were associated with an increased risk for adverse cardiovascular events (hazard ratio: 2.3) in the FHS cohort, suggesting that cardiovascular risk assessment in the general population can benefit from rare variant analysis.

Published
2012

33. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study

Author

John F. Thompson, Marju Orho-Melander, Mary Susan Burnett, Jürgen Schrezenmeir, Nour Eddine El Mokhtari, Christopher J. O'Donnell, Philipp S. Wild, Christina Willenborg, Stacey Gabriel, Yvonne T. van der Schouw, Maja Barbalić, Alistair S. Hall, Christopher Newton-Cheh, Michael Boehnke, Sonia S. Anand, Diederick E. Grobbee, Andreas Ziegler, Asif Rasheed, Bruna Gigante, Anne Tybjærg-Hansen, Heribert Schunkert, Kiran Musunuru, Jaume Marrugat, Vincent Mooser, Markku S. Nieminen, Pascal P. McKeown, Nicola Martinelli, Olaf H. Klungel, George Hindy, Cristen J. Willer, Anthonius de Boer, Li Chen, Diego Ardissino, Marja-Liisa Lokki, Ron Do, Karen L. Mohlke, Elena Gonzalez, John F. Peden, Shaun Purcell, Diether Lambrechts, Ruth Frikke-Schmidt, Mark J. Daly, Ida Surakka, Aarti Surti, Frans Van de Werf, Gina M. Peloso, Serkalem Demissie, Jolanda M. A. Boer, Gonçalo R. Abecasis, Aki S. Havulinna, W. M. Monique Verschuren, Hugh Watkins, Danish Saleheen, Bas J M Peters, Nilesh J. Samani, Inke R. König, Domenico Girelli, Markus Perola, Paul I.W. de Bakker, Juha Sinisalo, James C. Engert, Alexandre F.R. Stewart, Unnur Thorsteinsdottir, Keith A.A. Fox, Stefan Blankenberg, Muredach P. Reilly, Joseph M. Devaney, Anke-Hilse Maitland-van der Zee, Klaus Berger, Eric Boerwinkle, Marcus Fischer, Gudmundur Thorgeirsson, John A. Spertus, Clara C. Elbers, Daniel J. Rader, Stefan Schreiber, Arne Schäfer, Tanja Zeller, Erik Ingelsson, Arne Schillert, Jemma C. Hopewell, John Danesh, Ian Buysschaert, Toby Johnson, Samuli Ripatti, David S. Siscovick, Eric B. Rimm, Jeanette Erdmann, Sekar Kathiresan, Christian Hengstenberg, Olle Melander, Mingyao Li, Gudmar Thorleifsson, Roberto Elosua, Hilma Holm, Vera H.M. Deneer, Ruth McPherson, Benjamin F. Voight, Candace Guiducci, N. Charlotte Onland-Moret, Philippe M. Frossard, James P. Pirruccello, Cisca Wijmenga, Majken K. Jensen, Leena Peltonen, Ulf de Faire, Christopher Patterson, Diana Rubin, David Altshuler, Jose M. Ordovas, Eric L. Ding, Thomas M. Morgan, Pieter Willem Kamphuisen, Noël P. Burtt, Patrick Diemert, Robert Roberts, Pier Mannuccio Mannucci, Stephen E. Epstein, Stephen M. Schwartz, Kim Overvad, Monika Stoll, Veikko Salomaa, Robert Clarke, Kari Stefansson, Marten H. Hofker, L. Adrienne Cupples, Faculteit Medische Wetenschappen/UMCG, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Center for Liver, Digestive and Metabolic Diseases (CLDM), Cardiovascular Centre (CVC), and Vascular Ageing Programme (VAP)

Subjects
LOCI, Myocardial Infarction, 030204 cardiovascular system & hematology, chemistry.chemical_compound, 0302 clinical medicine, High-density lipoprotein, Gene Frequency, plasma HDL cholesterol, mendelian randomisation, MI, HDL cholesterol, single nucleotide polymorphism, Risk Factors, GENETIC-VARIANTS, ARTERY-DISEASE, Prospective Studies, Myocardial infarction, 0303 health sciences, myocardial infarction, ISCHEMIC CARDIOVASCULAR-DISEASE, General Medicine, 3. Good health, Cardiology, lipids (amino acids, peptides, and proteins), medicine.medical_specialty, Dalcetrapib, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, 03 medical and health sciences, Internal medicine, medicine, Humans, CORONARY-HEART-DISEASE, Genetic Predisposition to Disease, METAANALYSIS, 030304 developmental biology, BLOOD CHOLESTEROL, business.industry, Cholesterol, Cholesterol, HDL, Case-control study, Cholesterol, LDL, Lipase, Odds ratio, Mendelian Randomization Analysis, medicine.disease, ENDOTHELIAL LIPASE, ATHEROSCLEROSIS, chemistry, Case-Control Studies, business, HIGH-DENSITY-LIPOPROTEIN, Biomarkers, Evacetrapib
Abstract

BACKGROUND: High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal. METHODS: We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20,913 myocardial infarction cases, 95,407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12,482 cases of myocardial infarction and 41,331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol. FINDINGS: Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10(-13)) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84-0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88-1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58-0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68-1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45-1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69-2·69, p=2×10(-10)). INTERPRETATION: Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction. FUNDING: US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the German Federal Ministry of Education and Research.

Published
2012

34. Large-scale association analysis identifies new risk loci for coronary artery disease

Author

Benjamin F. Voight, Andrew D. Morris, G. Kees Hovingh, Anthony J. Balmforth, Hanneke Basart, Alistair S. Hall, Dominique Gauguier, Bok Ghee Han, Martina Müller-Nurasyid, Sarah Parish, Jarmo Virtamo, Christa Meisinger, Peter Wagner, George Dedoussis, Philipp S. Wild, Kari Stefansson, Jean-Baptiste Cazier, Kathleen Stirrups, Jiyoung Lee, Adrienne Cupples, Stavroula Kanoni, Danish Saleheen, Christian Hengstenberg, Svati H. Shah, Panos Deloukas, Anuj Goel, Stefan Blankenberg, Sian Tsung Tan, Alison H. Goodall, Tõnu Esko, Eric Boerwinkle, Gudmundur Thorgeirsson, Peter S. Braund, Joshua W. Knowles, Olle Melander, C. Ellen van der Schoot, Silke Rosinger, Maria Dimitriou, Wolfgang Koenig, Michael Boehnke, François Cambien, Per Lundmark, Dmitry Shungin, Wolfgang Kratzer, Pierre Zalloua, Reijo Laaksonen, Jean Ferrières, Villi Gudnason, Thorsten Kessler, Daniel J. Rader, Niclas Eriksson, Dominique Arveiler, Natalie R. van Zuydam, Kari Kuulasmaa, N. William Rayner, Sarah E. Hunt, Gudmar Thorleifsson, Jeanette Erdmann, Samuli Ripatti, Tsun-Po Yang, George A. Wells, Terho Lehtimäki, Kjell Nikus, Pierre Fontanillas, Jorg Hager, Martin Farrall, Jemma C. Hopewell, Frank Kee, Juha Sinisalo, Christopher J. O'Donnell, Asif Rasheed, Mika Kähönen, Genovefa Kolovou, Seraya Maouche, Suzanne Rafelt, Cordelia Langford, Winfried März, Leo-Pekka Lyytikäinen, Christina Willenborg, Weihua Zhang, Kati Kristiansson, Hyo-Soo Kim, Weang K. Ho, Jeong E. Park, Mohan U. Sivananthan, Moritz P. Rumpf, Markku Laakso, Klaus Stark, Philippe Amouyel, Paul W. Franks, Andres Metspalu, Anders Franco-Cereceda, Manjinder S. Sandhu, Nour Eddine El Mokhtari, Nicholas J. Wareham, Robert Roberts, Veikko Salomaa, Thomas Illig, Tomi Pastinen, Robert Clarke, Christof Burgdorf, Leif Groop, Devin Absher, Yangsoo Jang, Mark I. McCarthy, Bernhard O. Boehm, Per Eriksson, Nilesh J. Samani, Inke R. König, Stefan Schreiber, Karin Leander, Simone Claudi-Boehm, Ci Song, Benjamin A. Goldstein, Stephen E. Epstein, Andreas Ziegler, Stanley L. Hazen, Arne Schäfer, Elin Grundberg, Sekar Kathiresan, John R. Thompson, Unnur Thorsteinsdottir, Muredach P. Reilly, Heribert Schunkert, Rory Collins, Thomas Quertermous, Jong-Young Lee, John Danesh, John C. Chambers, Marco M Ferrario, Carlos Iribarren, Claudia Langenberg, Hilma Holm, Rona J. Strawbridge, Alan S. Go, Cristen J. Willer, Ron Do, Emmi Tikkanen, Abbas Dehghan, Evelin Mihailov, Lindsay L. Waite, Patrick Diemert, Willem H. Ouwehand, Eric E. Schadt, Diana Rubin, David Altshuler, Marcus E. Kleber, Markus Perola, Alexandre F.R. Stewart, Jaspal S. Kooner, Themistocles L. Assimes, Inês Barroso, Bruna Gigante, Göran Hallmans, Marja-Liisa Lokki, Aki S. Havulinna, Anders Hamsten, Agneta Siegbahn, Lasse Folkersen, Erik Ingelsson, Martina E. Zimmermann, Colin N. A. Palmer, Paolo Brambilla, Ann-Christine Syvänen, Alun Evans, Åsa Johansson, John F. Peden, Alex S. F. Doney, Hugh Watkins, Johanna Kuusisto, Anders Lundmark, David G. Cox, Hyun Min Kang, Lars Lind, Krista Fischer, Markku S. Nieminen, Annette Peters, Norman Klopp, Stefan Gustafsson, Lars Wallentin, Nancy L. Pedersen, David-Alexandre Trégouët, Ulf de Faire, Deloukas, P, Kanoni, S, Willenborg, C, Farrall, M, Assimes, T, Thompson, J, Ingelsson, E, Saleheen, D, Erdmann, J, Goldstein, B, Stirrups, K, König, I, Cazier, J, Johansson, Å, Hall, A, Lee, J, Willer, C, Chambers, J, Esko, T, Folkersen, L, Goel, A, Grundberg, E, Havulinna, A, Ho, W, Hopewell, J, Eriksson, N, Kleber, M, Kristiansson, K, Lundmark, P, Lyytikäinen, L, Rafelt, S, Shungin, D, Strawbridge, R, Thorleifsson, G, Tikkanen, E, Van Zuydam, N, Voight, B, Waite, L, Zhang, W, Ziegler, A, Absher, D, Altshuler, D, Balmforth, A, Barroso, I, Braund, P, Burgdorf, C, Claudi Boehm, S, Cox, D, Dimitriou, M, Do, R, Doney, A, El Mokhtari, N, Eriksson, P, Fischer, K, Fontanillas, P, Franco Cereceda, A, Gigante, B, Groop, L, Gustafsson, S, Hager, J, Hallmans, G, Han, B, Hunt, S, Kang, H, Illig, T, Kessler, T, Knowles, J, Kolovou, J, Kuusisto, J, Langenberg, C, Langford, C, Leander, K, Lokki, M, Lundmark, A, Mccarthy, M, Meisinger, C, Melander, O, Mihailov, E, Maouche, S, Morris, A, Müller Nurasyid, M, Nikus, K, Peden, J, Rayner, N, Rasheed, A, Rosinger, S, Rubin, D, Rumpf, M, Schäfer, A, Sivananthan, M, Song, C, Stewart, A, Tan, S, Thorgeirsson, G, van der Schoot, C, Wagner, P, Wells, G, Wild, P, Yang, T, Amouyel, P, Arveiler, D, Basart, H, Boehnke, M, Boerwinkle, E, Brambilla, P, Cambien, F, Cupples, A, de Faire, U, Dehghan, A, Diemert, P, Epstein, S, Evans, A, Ferrario, M, Ferrières, J, Gauguier, D, Go, A, Goodall, A, Gudnason, V, Hazen, S, Holm, H, Iribarren, C, Jang, Y, Kähönen, M, Kee, F, Kim, H, Klopp, N, Koenig, W, Kratzer, W, Kuulasmaa, K, Laakso, M, Laaksonen, R, Lind, L, Ouwehand, W, Parish, S, Park, J, Pedersen, N, Peters, A, Quertermous, T, Rader, D, Salomaa, V, Schadt, E, Shah, S, Sinisalo, J, Stark, K, Stefansson, K, Trégouët, D, Virtamo, J, Wallentin, L, Wareham, N, Zimmermann, M, Nieminen, M, Hengstenberg, C, Sandhu, M, Pastinen, T, Syvänen, A, Hovingh, G, Dedoussis, G, Franks, P, Lehtimäki, T, Metspalu, A, Zalloua, P, Siegbahn, A, Schreiber, S, Ripatti, S, Blankenberg, S, Perola, M, Clarke, R, Boehm, B, O’Donnell, C, Reilly, M, März, W, Collins, R, Kathiresan, S, Hamsten, A, Kooner, J, Thorsteinsdottir, U, Danesh, J, Palmer, C, Roberts, R, Watkins, H, Schunkert, H, Samani, N, Landsteiner Laboratory, Clinical Haematology, Other departments, ACS - Amsterdam Cardiovascular Sciences, and Vascular Medicine

Subjects
Adult, Asian Continental Ancestry Group, Male, Candidate gene, BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Population, European Continental Ancestry Group, Quantitative Trait Loci, CAD, Genome-wide association study, Single-nucleotide polymorphism, Coronary Artery Disease, 030204 cardiovascular system & hematology, Biology, Quantitative trait locus, Bioinformatics, Polymorphism, Single Nucleotide, Article, White People, coronary artery disease, risk loci, Cell Line, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Asian People, Risk Factors, medicine, Humans, genetics, Gene Regulatory Networks, Genetic Predisposition to Disease, cardiovascular diseases, Polymorphism, education, 030304 developmental biology, Genetic association, Aged, Genetics, 0303 health sciences, education.field_of_study, Adult, Aged, Asian Continental Ancestry Group, Cell Line, Coronary Artery Disease, genetics, European Continental Ancestry Group, genetics, Female, Gene Regulatory Networks, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, Single Nucleotide, Middle Aged, medicine.disease, 3. Good health, Female, Genome-Wide Association Study
Abstract

Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r 2 < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways. © 2013 Nature America, Inc. All rights reserved.

Published
2012
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35. Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease

Author

Mélissa Beaudoin, Stephan Ripke, Jonas Halfvarson, Leif Törkvist, Dermot P.B. McGovern, Caroline Lagacé, Todd Green, David Ellinghaus, Mauro D'Amato, Andrew Kirby, Manuel A. Rivas, Steven R. Brant, Ramnik J. Xavier, Stacey Gabriel, Guillaume Lettre, Joshua M. Korn, Philippe Goyette, Finny G Kuruvilla, Clarence K. Zhang, Noël P. Burtt, Agnes Gardet, Richard H. Duerr, Timothy Fennell, Yashoda Sharma, Benjamin M. Neale, Andre Franke, Ken Sin Lo, David Altshuler, Gabrielle Boucher, Talin Haritunians, Marla Dubinsky, Phil Schumm, John D. Rioux, Mark J. Daly, Judy H. Cho, Mark S. Silverberg, Anna Latiano, Christine Stevens, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Gastroenterology and Hepatology

Subjects
RNA Splicing, Nod2 Signaling Adaptor Protein, Genome-wide association study, Biology, Molecular gastro-enterology and hepatology Pathogenesis and modulation of inflammation [IGMD 2], Inflammatory bowel disease, Article, Cell Line, PTPN22, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genotyping, 030304 developmental biology, Genetic association, 0303 health sciences, Case-control study, Receptors, Interleukin, Sequence Analysis, DNA, Odds ratio, Inflammatory Bowel Diseases, medicine.disease, 3. Good health, Case-Control Studies, 030220 oncology & carcinogenesis, Genome-Wide Association Study, Common disease-common variant
Abstract

Item does not contain fulltext More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 x 10(-16), odds ratio approximately 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models. 01 november 2011

Published
2011

36. Updated Genetic Score Based on 34 Confirmed Type 2 Diabetes Loci Is Associated With Diabetes Incidence and Regression to Normoglycemia in the Diabetes Prevention Program

Author

William C. Knowler, Richa Saxena, James B. Meigs, Richard F. Hamman, Marie-France Hivert, David Altshuler, Jose C. Florez, Steven E. Kahn, Paul W. Franks, Jarred B. McAteer, Kathleen A. Jablonski, Leigh Perreault, and Steven M. Haffner

Subjects
medicine.medical_specialty, Genotype, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Type 2 diabetes, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Weight loss, Internal medicine, Diabetes mellitus, Weight Loss, Internal Medicine, medicine, Genetics, Humans, Hypoglycemic Agents, 030304 developmental biology, 0303 health sciences, Glucose tolerance test, medicine.diagnostic_test, business.industry, Incidence (epidemiology), Glucose Tolerance Test, medicine.disease, Regression, Metformin, 3. Good health, Exercise Therapy, Increased risk, Endocrinology, Diabetes Mellitus, Type 2, medicine.symptom, business, medicine.drug
Abstract

OBJECTIVE Over 30 loci have been associated with risk of type 2 diabetes at genome-wide statistical significance. Genetic risk scores (GRSs) developed from these loci predict diabetes in the general population. We tested if a GRS based on an updated list of 34 type 2 diabetes–associated loci predicted progression to diabetes or regression toward normal glucose regulation (NGR) in the Diabetes Prevention Program (DPP). RESEARCH DESIGN AND METHODS We genotyped 34 type 2 diabetes–associated variants in 2,843 DPP participants at high risk of type 2 diabetes from five ethnic groups representative of the U.S. population, who had been randomized to placebo, metformin, or lifestyle intervention. We built a GRS by weighting each risk allele by its reported effect size on type 2 diabetes risk and summing these values. We tested its ability to predict diabetes incidence or regression to NGR in models adjusted for age, sex, ethnicity, waist circumference, and treatment assignment. RESULTS In multivariate-adjusted models, the GRS was significantly associated with increased risk of progression to diabetes (hazard ratio [HR] = 1.02 per risk allele [95% CI 1.00–1.05]; P = 0.03) and a lower probability of regression to NGR (HR = 0.95 per risk allele [95% CI 0.93–0.98]; P < 0.0001). At baseline, a higher GRS was associated with a lower insulinogenic index (P < 0.001), confirming an impairment in β-cell function. We detected no significant interaction between GRS and treatment, but the lifestyle intervention was effective in the highest quartile of GRS (P < 0.0001). CONCLUSIONS A high GRS is associated with increased risk of developing diabetes and lower probability of returning to NGR in high-risk individuals, but a lifestyle intervention attenuates this risk.

Published
2011

37. A Genome-Wide Association Study Identifies LIPA as a Susceptibility Gene for Coronary Artery Disease

Author

Juergen Schrezenmeir, Heidi Rossmann, Joshua C. Bis, Tanja Zeller, Heinz Erich Wichmann, Sandra Wilde, Jeanette Erdmann, Serkalem Demissie, Wibke Reinhard, Roberto Elosua, Arne Schillert, Vilmundur Gudnason, Albert Hofman, Sekar Kathiresan, Philipp S. Wild, Christoph Bickel, François Cambien, Stefan Schreiber, Mary Susan Burnett, Eric Boerwinkle, Klaus Stark, Nour Eddine El Mokthari, Stefan Blankenberg, Mingyao Li, Veikko Salomaa, Medea S. Eleftheriadis, Marcus E. Kleber, Dominique Arveiler, Alun Evans, Kaisa Silander, Jarmo Virtamo, Michael M. Hoffmann, Arne Schäfer, Andreas Ziegler, Patrick Diemert, Till Keller, Aaron R. Folsom, Peter S. Braund, Annette Peters, Karl J. Lackner, Nehal N. Mehta, Stephen M. Schwartz, Nilesh J. Samani, Inke R. König, Heribert Schunkert, Renate B. Schnabel, Jens Baumert, L. Adrienne Cupples, André G. Uitterlinden, Tamara B. Harris, Muredach P. Reilly, Per-Gunnar Wiklund, Hans J. Rupprecht, Maja Barbalić, Jaqueline C M Witteman, Frank Kee, Jean Ferrières, Edith Lubos, Hendrik B. Sager, David S. Siscovick, Liming Qu, Norman Klopp, Daniel J. Rader, Thomas Münzel, Joseph M. Devaney, Hakon Hakonarson, Benjamin F. Voight, Stephen E. Epstein, Emmanuelle Yon, Albert V. Smith, Silke Szymczak, Claire Perret, Christoph Sinning, Diana Rubin, Maryam Kavousi, David Altshuler, Laurence Tiret, Carole Proust, Christopher J. O'Donnell, John R. Thompson, Winfried März, Olli Saarela, Arne Deiseroth, Thomas Illig, Philippe Amouyel, Christian Hengstenberg, Olle Melander, Kari Kuulasmaa, Alistair S. Hall, Epidemiology, and Internal Medicine

Subjects
Genomics, Genome-wide association study, Coronary Artery Disease, 030204 cardiovascular system & hematology, Biology, Polymorphism, Single Nucleotide, Article, Monocytes, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Genetic variation, medicine, Genetics, coronary artery disease, genome-wide association studies, gene expression, genetic variation, genomics, eQTL, eSNP, LIPA, Humans, Genetic Predisposition to Disease, Genetics(clinical), RNA, Messenger, Gene, Genetics (clinical), 030304 developmental biology, Genetic association, 0303 health sciences, Chromosomes, Human, Pair 10, Gene Expression Profiling, Genetic Variation, Sterol Esterase, medicine.disease, Gene expression profiling, Case-Control Studies, Expression quantitative trait loci, Endothelium, Vascular, Cardiology and Cardiovascular Medicine, Genome-Wide Association Study
Abstract

Background— eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD). Methods and Results— In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single-nucleotide polymorphisms (SNPs) that were associated with CAD at P −3 . Subsequent in silico and wet-laboratory replication stages and a final meta-analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene ( P =3.7×10 −8 ; odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript ( P =1.3×10 −96 ). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function ( P =4.4×10 −3 ). Conclusions— The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA , located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD.

Published
2011
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38. Common Variants in 40 Genes Assessed for Diabetes Incidence and Response to Metformin and Lifestyle Intervention in the Diabetes Prevention Program

Author

Kathleen A. Jablonski, Toni I. Pollin, Jarred B. McAteer, Paul I.W. de Bakker, Sarah E. Fowler, William C. Knowler, Jose C. Florez, Richa Saxena, David Altshuler, Alan R. Shuldiner, Paul W. Franks, and Robert L. Hanson

Subjects
Adult, Hemeproteins, Male, medicine.medical_specialty, Genotype, Organic Cation Transport Proteins, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Genome-wide association study, Polymorphism, Single Nucleotide, Body Mass Index, law.invention, 03 medical and health sciences, Diabetes mellitus genetics, 0302 clinical medicine, Randomized controlled trial, law, Diabetes mellitus, Internal medicine, Genetic variation, Genetics, Diabetes Mellitus, Ethnicity, Internal Medicine, medicine, Humans, Life Style, 030304 developmental biology, 0303 health sciences, business.industry, Incidence, Incidence (epidemiology), Racial Groups, Genetic Variation, Middle Aged, medicine.disease, Metformin, 3. Good health, Endocrinology, Diabetes Mellitus, Type 2, Female, business, Body mass index, Genome-Wide Association Study, medicine.drug
Abstract

OBJECTIVE Genome-wide association studies have begun to elucidate the genetic architecture of type 2 diabetes. We examined whether single nucleotide polymorphisms (SNPs) identified through targeted complementary approaches affect diabetes incidence in the at-risk population of the Diabetes Prevention Program (DPP) and whether they influence a response to preventive interventions. RESEARCH DESIGN AND METHODS We selected SNPs identified by prior genome-wide association studies for type 2 diabetes and related traits, or capturing common variation in 40 candidate genes previously associated with type 2 diabetes, implicated in monogenic diabetes, encoding type 2 diabetes drug targets or drug-metabolizing/transporting enzymes, or involved in relevant physiological processes. We analyzed 1,590 SNPs for association with incident diabetes and their interaction with response to metformin or lifestyle interventions in 2,994 DPP participants. We controlled for multiple hypothesis testing by assessing false discovery rates. RESULTS We replicated the association of variants in the metformin transporter gene SLC47A1 with metformin response and detected nominal interactions in the AMP kinase (AMPK) gene STK11, the AMPK subunit genes PRKAA1 and PRKAA2, and a missense SNP in SLC22A1, which encodes another metformin transporter. The most significant association with diabetes incidence occurred in the AMPK subunit gene PRKAG2 (hazard ratio 1.24, 95% CI 1.09–1.40, P = 7 × 10−4). Overall, there were nominal associations with diabetes incidence at 85 SNPs and nominal interactions with the metformin and lifestyle interventions at 91 and 69 mostly nonoverlapping SNPs, respectively. The lowest P values were consistent with experiment-wide 33% false discovery rates. CONCLUSIONS We have identified potential genetic determinants of metformin response. These results merit confirmation in independent samples.

Published
2010

39. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Author

Kenneth Rice, Amy J. Swift, Veronique Vitart, Lu Qi, Kaisa Silander, Olivier Le Bacquer, Laura Crisponi, David S. Siscovick, Bo Isomaa, Anne U. Jackson, Anke Tönjes, Richard N. Bergman, Rosa Maria Roccasecca, Luigi Ferrucci, Narisu Narisu, Kari Stefansson, Holly E. Syddall, Giuseppe Paolisso, Kim L. Ward, Paul Elliott, Scott M. Grundy, Paul Johnson, Jerome I. Rotter, Philippe Froguel, James B. Meigs, George Davey Smith, Andrew T. Hattersley, Leena Peltonen, Eric J.G. Sijbrands, Serena Sanna, María TeresaMartínez-Larrad, David Altshuler, Harald Grallert, Caroline S. Fox, Nita G. Forouhi, Dorret I. Boomsma, Harry Campbell, Jean Tichet, Angelo Scuteri, Aroon D. Hingorani, Daniel S. Pearson, Meena Kumari, Silvia Naitza, Shah Ebrahim, Manjinder S. Sandhu, Jose C. Florez, Cyrus Cooper, David M. Nathan, Joseph Hung, Fredrik Karpe, Ozren Polasek, Philip J. Barter, Ruth McPherson, Benjamin F. Voight, Wolfgang Rathmann, Abbas Dehghan, Udo Seedorf, Beverley M. Shields, Antti Jula, Pau Navarro, Josephine M. Egan, Rune R. Frants, Leif Groop, Gunnar Sigursson, Seppo Koskinen, Vincent Mooser, François Pattou, Jing Hua Zhao, Irene Pichler, John F. Peden, Göran Hallmans, Toshiko Tanaka, Ruth J. F. Loos, Peter Kovacs, Andrew D. Morris, Cécile Lecoeur, Jeffrey R. O'Connell, Massimo Mangino, Nicole Vogelzangs, Rhian Gwilliam, Gordon H. Williams, Carina Zabena, Naomi Hammond, Amélie Bonnefond, Björn Zethelius, Joachim Spranger, Nancy L. Pedersen, Christopher J. Groves, Nicholas J. Timpson, George Dedoussis, Veikko Salomaa, Peter Henneman, Andrew Walley, Serge Hercberg, Ian N. M. Day, Simon Heath, Matt Neville, Alex S. F. Doney, Robert Clarke, Olov Rolandsson, Panos Deloukas, Eric Boerwinkle, Y. AnteroKesaniemi, Mike Sampson, Gerard Waeber, Sven Bergmann, Ben A. Oostra, Manuel Serrano-Ríos, Mandy van Hoek, Christine Cavalcanti-Proença, Anna L. Gloyn, Ulla Sovio, Andrew P. Morris, Anneli Pouta, Amanda J. Bennett, Paul Scheet, Peter Schwarz, Jaakko Tuomilehto, Hugh Watkins, Johanna Kuusisto, Denis Rybin, Anna LiisaHartikainen, Maria GraziaFranzosi, Unnur Thorsteinsdottir, Rafn Benediktsson, Alan F. Wright, Colin N. Apalmer, Anuj Goel, Yavuz Ariyurek, Lars Lind, Robert Sladek, Stefan R. Bornstein, Reedik Mägi, Laila Simpson, Tim D. Spector, Paul W. Franks, Nicholas L. Smith, John R. B. Perry, Peter Vollenweider, Suzannah Bumpstead, Ruth E. Pakyz, Christa Meisinger, Alan R. Shuldiner, Josée Dupuis, Man Li, Eric J. Brunner, Francis S. Collins, Torben Hansen, James F. Wilson, Guangju Zhai, Igor Rudan, Nicole L. Glazer, Marco Orrù, Pierre Meneton, Knut Borch-Johnsen, Eleanor Wheeler, Gonçalo R. Abecasis, Mark I. McCarthy, Jouke JanHottenga, Inga Prokopenko, Ping An, Jérôme Delplanque, Albert Hofman, Andrew B. Singleton, Gabe Crawford, Thomas A. Buchanan, Avan Aihie Sayer, Richard M. Watanabe, David Schlessinger, A C Fedson, André G. Uitterlinden, Frank B. Hu, Jaqueline C. MWitteman, Dhiraj Varma, Ingrid B. Borecki, Sutapa Mukherjee, Murielle Bochud, Barbara Thorand, Christian Gieger, Lori L. Bonnycastle, Stephen J. Sharp, Markus Perola, Caroline Hayward, Kristin Ardlie, J. Graessler, Robert W. Mahley, Toby Johnson, Jian'an Luan, Joshua C. Randall, Cornelia M. van Duijn, Samuli Ripatti, Ko Willems van Dijk, Valgerdur Steinthorsdottir, Yurii S. Aulchenko, G. Mark Lathrop, Christian Dina, Eleftheria Zeggini, Cecilia M. Lindgren, Stavroula Kanoni, Timothy M. Frayling, Dawn M. Waterworth, Marika Kaakinen, Timo T. Valle, Diana Zelenika, Yii Der IdaChen, Angela Silveira, Nigel W. Rayner, Aimo Ruokonen, Yun Li, Cristian Pattaro, Annelli Sandbæk, Richa Saxena, Danielle Posthuma, Steven A. McCarroll, Niels Grarup, Samy Hadjadj, Pilar Galan, Xijing Han, Lyle J. Palmer, Ulf Gyllensten, Peter P. Pramstaller, Manuela Uda, Jarred B. McAteer, Brenda W.J.H. Penninx, Debbie A Lawlor, Torben Jørgensen, Beatrice Knight, Yvonne Böttcher, Claudia Langenberg, Nicole Soranzo, Ghislain Rocheleau, Erik Ingelsson, Mario A. Morken, Michael Roden, Felicity Payne, David R. Hillman, Michael Marmot, Karen L. Mohlke, Heather M. Stringham, Bruce M. Psaty, Gudmar Thorleifsson, Yoav Ben-Shlomo, Inês Barroso, W. H. Linda Kao, James S. Pankow, Valeriya Lyssenko, Nicholas J. Wareham, Tiinamaija Tuomi, Ann ChristineSyvänen, Braxton D. Mitchell, Alisa K. Manning, Mika Kivimäki, Peter Wagner, Praveen Sethupathy, G. BragiWalters, Jaakko Kaprio, Kijoung Song, Marjo Riitta-Järvelin, Michael A. Province, Andrew A. Hicks, Marilyn C. Cornelis, Sarah H. Wild, David Meyre, Guillaume Charpentier, Patrik K. E. Magnusson, David Melzer, Jennie Hui, Peter Shrader, Michael Stumvoll, Mark O. Goodarzi, Michael R. Erdos, Oluf Pedersen, Andreas Pfeiffer, Augustine Kong, Christian Herder, Laura J. Scott, John W. GYarnell, Kirsten Ohm Kyvik, Beverley Balkau, Antje Fischer-Rosinsky, Gonneke Willemsen, Thomas Illig, Neelam Hassanali, Markku Laakso, Michael Boehnke, John Beilby, Christopher S. Franklin, Fernando Rivadeneira, M. Carola Zillikens, Michael N. Weedon, Antonio Cao, Mark E. Cooper, Simon C. Potter, Eco J. C. de Geus, H.-Erich Wichmann, Amanda F. Elliott, Lachlan J. McOin, Sophie Visvikis-Siest, Thomas Sparsø, Laura J. McCulloch, Taina K. Lajunen, Peter S. Chines, Nabila Bouatia-Naji, Medical Research Council (MRC), Biological Psychology, Functional Genomics, Neuroscience Campus Amsterdam - Anxiety & Depression, Neuroscience Campus Amsterdam - Attention & Cognition, EMGO+ - Mental Health, Ophthalmology, Epidemiology, Clinical Genetics, Dermatology, Internal Medicine, DIAGRAM Consortium, GIANT Consortium, Global BPgen Consortium, Anders Hamsten on behalf of Procardis Consortium, MAGIC investigators, Human genetics, Psychiatry, EMGO - Mental health, NCA - Attention & Cognition, and NCA - Anxiety & Depression

Subjects
Blood Glucose, Netherlands Twin Register (NTR), Candidate gene, Genome-wide association study, Type 2 diabetes, CIRCADIAN CLOCK, TRIGLYCERIDE LEVELS, 0302 clinical medicine, Delta-5 Fatty Acid Desaturase, Databases, Genetic, Homeostasis, GENETICS & HEREDITY, Anders Hamsten on behalf of Procardis Consortium, Child, Genetics, PLASMA-GLUCOSE, 0303 health sciences, Glucokinase regulatory protein, COMMON VARIANTS, 11 Medical And Health Sciences, Fasting, MAGIC investigators, 3. Good health, MODEL ASSESSMENT, Life Sciences & Biomedicine, Adult, medicine.medical_specialty, ESSENTIAL COMPONENTS, Adolescent, DNA Copy Number Variations, Alleles, Blood Glucose/genetics, Blood Glucose/metabolism, DNA Copy Number Variations/genetics, Diabetes Mellitus, Type 2/genetics, Fasting/blood, Gene Expression Regulation, Genetic Loci/genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Homeostasis/genetics, Humans, Meta-Analysis as Topic, Polymorphism, Single Nucleotide/genetics, Quantitative Trait Loci/genetics, Quantitative Trait, Heritable, Reproducibility of Results, Quantitative Trait Loci, 030209 endocrinology & metabolism, Biology, DIAGRAM Consortium, INSULIN-SECRETION, Polymorphism, Single Nucleotide, Article, Fasting glucose, 03 medical and health sciences, Insulin resistance, SDG 3 - Good Health and Well-being, Diabetes mellitus, Internal medicine, genome wide association study, glucose, diabetes type 2, medicine, GIANT Consortium, Allele, GENOME-WIDE ASSOCIATION, Global BPgen Consortium, 030304 developmental biology, Glycemic, Science & Technology, genome-wide association beta-cell dysfunction plasma-glucose insulin-secretion triglyceride levels essential components model assessment common variants circadian clock disease risk, DISEASE RISK, 06 Biological Sciences, medicine.disease, Endocrinology, Diabetes Mellitus, Type 2, Genetic Loci, biology.protein, BETA-CELL DYSFUNCTION, Developmental Biology
Abstract

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46, 186 nondiabetic participants. Follow-up of 25 loci in up to 76, 558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

Published
2010
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40. Donor-recipient mismatch for common gene deletion polymorphisms in graft-versus-host disease

Author

Edus H. Warren, Steven A. McCarroll, Paul J. Martin, Liisa Volin, Barry E. Storer, Stephanie J. Lee, Jukka Partanen, Robert J. Soiffer, Lue Ping Zhao, James E. Bradner, David Altshuler, Jerome Ritz, Hannu Turpeinen, Joseph H. Antin, David Ginsburg, John A. Hansen, Aarno Palotie, Tapani Ruutu, Bo Zhang, and Shannon D Chilewski

Subjects
Male, medicine.medical_treatment, Graft vs Host Disease, Locus (genetics), Hematopoietic stem cell transplantation, Human leukocyte antigen, Biology, Article, Cohort Studies, Minor Histocompatibility Antigens, 03 medical and health sciences, 0302 clinical medicine, HLA Antigens, Genetics, Minor histocompatibility antigen, medicine, Humans, Glucuronosyltransferase, Bone Marrow Transplantation, 030304 developmental biology, 0303 health sciences, Polymorphism, Genetic, Genome, Human, Alloimmunity, Hematopoietic Stem Cell Transplantation, medicine.disease, 3. Good health, Histocompatibility, Transplantation, surgical procedures, operative, Graft-versus-host disease, Immunology, Female, Gene Deletion, 030215 immunology
Abstract

Transplantation and pregnancy, in which two diploid genomes reside in one body, can each lead to diseases in which immune cells from one individual target antigens encoded in the other's genome. One such disease, graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT, or bone marrow transplant), is common even after transplants between HLA-identical siblings, indicating that cryptic histocompatibility loci exist outside the HLA locus. The immune system of an individual whose genome is homozygous for a gene deletion could recognize epitopes encoded by that gene as alloantigens. Analyzing common gene deletions in three HSCT cohorts (1,345 HLA-identical sibling donor-recipient pairs), we found that risk of acute GVHD was greater (odds ratio (OR) = 2.5; 95% confidence interval (CI) 1.4-4.6) when donor and recipient were mismatched for homozygous deletion of UGT2B17, a gene expressed in GVHD-affected tissues and giving rise to multiple histocompatibility antigens. Human genome structural variation merits investigation as a potential mechanism in diseases of alloimmunity.

Published
2009

41. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes

Author

Andrew Paterson, Neeraj Kumar, Luis Castaño, Jinny Willis, Valdis Pirags, David Altshuler, Farren Briggs, Neil Walker, Ondrej Cinek, Helen Schuilenburg, Francisco Javier Ampudia Blasco, Claire Vandiedonck, Mark A. Hall, Ana M Wägner, Xiaoying Li, Flemming Pociot, Didac Mauricio, Vaidotas Urbanavicius, Jennifer Couper, Adam Kretowski, Deborah Smyth, Professor David Dunger, Federico Vázquez, Ian Nicholson, Ellen Schofield, John Todd, Angela Simpson, Ingrid Kockum, Mikael Knip, Tadej Battelino, Thomas Brodnicki, Patrick Concannon, Jesús Argente, Johnny Ludvigsson, Peter Colman, Gurvinder Kaur, Vincent Plagnol, Oliver Burren, Rohana Abdul Ghani, Marta Hernández, William McLaren, Alessandro Doria, Raquel Corripio, Stephen Rich, Daniel Metzger, Jesper Johannesen, Steven Willi, Cécile JULIER, Vallo Tillmann, Bart Van der Auwera, Pathology/molecular and cellular medicine, and Diabetes Pathology & Therapy

Subjects
Male, Candidate gene, Interferon-Induced Helicase, IFIH1, Endocrinology, Diabetes and Metabolism, Genome-wide association study, Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics, DEAD-box RNA Helicases, 0302 clinical medicine, Chromosomes, Human, Pair 17/genetics, HLA Antigens, Genotype, CTLA-4 Antigen, Chromosomes, Human, Pair 2/genetics, Genetics, 0303 health sciences, Antigens, CD/genetics, Chromosome Mapping, HLA Antigens/genetics, Polymorphism, Single Nucleotide/genetics, 3. Good health, Chromosomes, Human, Pair 1/genetics, DEAD-box RNA Helicases/genetics, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 2, Meta-analysis, Female, Algorithms, 030209 endocrinology & metabolism, Locus (genetics), CLEC16A, DNA/genetics, Biology, Polymorphism, Single Nucleotide, Risk Assessment, Article, PTPN22, 03 medical and health sciences, Meta-Analysis as Topic, Antigens, CD, medicine, Humans, Family, 030304 developmental biology, Type 1 diabetes, Siblings, Protein Tyrosine Phosphatase, Non-Receptor Type 22, DNA, medicine.disease, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 1/epidemiology, Chromosome Mapping/methods, Chromosomes, Human, Pair 17, Genome-Wide Association Study
Abstract

Type 1 diabetes (T1D) is a common autoimmune disorder that arises from the action of multiple genetic and environmental risk factors. We report the findings of a new genome-wide association study of T1D, combined in a meta-analysis with two previously published studies. The total sample set included 7,514 cases and 9,045 reference samples. Forty-one distinct genomic locations provided evidence for association to T1D in the meta-analysis (P < 10-6). After excluding previously reported associations, 27 regions were further tested in an independent set of 4,267 cases, 4,463 controls and 2,319 affected sib-pair (ASP) families. Of these, 18 regions were replicated (P < 0.01; overall P < 5 × 10-8) and four additional regions provided nominal evidence of replication (P < 0.05). The many new candidate genes suggested by these results include IL10, IL19, IL20, GLIS3, CD69 and IL27.

Published
2009

42. Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion

Author

Michael Boehnke, Peter M. Nilsson, Marco Bugliani, Malin Fex, Johan G. Eriksson, Jaakko Tuomilehto, Nicolo Pulizzi, Richard M. Watanabe, Markku Laakso, Piero Marchetti, Peter Spégel, Cecilia Nagorny, Anna Jonsson, Valeriya Lyssenko, Bo Isomaa, Anne U. Jackson, Nils Wierup, Tiinamaija Tuomi, Hindrik Mulder, Richa Saxena, Frank Sundler, Michael R. Erdos, Leif Groop, Johanna Kuusisto, and David Altshuler

Subjects
Male, endocrine system, medicine.medical_specialty, endocrine system diseases, medicine.medical_treatment, Receptors, Melatonin, 030209 endocrinology & metabolism, Type 2 diabetes, Biology, Polymorphism, Single Nucleotide, Article, Cohort Studies, Melatonin, Islets of Langerhans, Mice, 03 medical and health sciences, Pineal gland, 0302 clinical medicine, Internal medicine, Diabetes mellitus, Insulin Secretion, Genetics, medicine, Animals, Humans, Insulin, Genetic Predisposition to Disease, Aged, 030304 developmental biology, 0303 health sciences, Receptor, Melatonin, MT2, Middle Aged, medicine.disease, Rats, Insulin oscillation, Protein Transport, Endocrinology, medicine.anatomical_structure, Diabetes Mellitus, Type 2, Gene Expression Regulation, Melatonin receptor 1B, Female, Hormone, medicine.drug
Abstract

Genome wide association studies revealed that variation in the Melatonin Receptor 1B gene (MTNR1B) is associated with insulin and glucose concentrations. Here we show that the risk genotype of this SNP predicts future type 2 diabetes (T2D) in two large prospective studies. Specifically, the risk genotype was associated with impairment of early insulin response to both oral and intravenous glucose and with faster deterioration of insulin secretion over time. We also show that the Melatonin Receptor 1B mRNA is expressed in human islets, and immunocytochemistry confirms that it is primarily localized in β-cells in islets. Non-diabetic individuals carrying the risk allele and patients with T2D showed increased expression of the receptor in islets. Insulin release from clonal β-cells in response to glucose was inhibited in the presence of melatonin. These data suggest that the circulating hormone melatonin, which is predominantly released from the pineal gland in the brain, is involved in the pathogenesis of T2D. Given the increased expression of Melatonin Receptor 1B in individuals at risk of T2D, the pathogenic effects are likely exerted via a direct inhibitory effect on β-cells. In view of these results, blocking the melatonin ligand-receptor system could be a therapeutic avenue in T2D.

Published
2009
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43. Extension of Type 2 Diabetes Genome-Wide Association Scan Results in the Diabetes Prevention Program

Author

Allan F, Moore, Kathleen A, Jablonski, Jarred B, McAteer, Richa, Saxena, Toni I, Pollin, Paul W, Franks, Robert L, Hanson, Alan R, Shuldiner, William C, Knowler, David, Altshuler, and Jose C, Florez

Subjects
Endocrinology, Diabetes and Metabolism, Quantitative Trait Loci, 030209 endocrinology & metabolism, Zinc Transporter 8, Type 2 diabetes, Biology, Quantitative trait locus, N-Acetylglucosaminyltransferases, Bioinformatics, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, Gene Frequency, Risk Factors, Diabetes mellitus, Genetics, Internal Medicine, medicine, Humans, Cation Transport Proteins, Life Style, CDKAL1, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p15, 030304 developmental biology, Glycemic, Homeodomain Proteins, tRNA Methyltransferases, 0303 health sciences, Incidence, Incidence (epidemiology), RNA-Binding Proteins, Cyclin-Dependent Kinase 5, Genomics, Middle Aged, medicine.disease, 3. Good health, TRNA Methyltransferases, Black or African American, Diabetes Mellitus, Type 2, Transcription Factors
Abstract

OBJECTIVE— Genome-wide association scans (GWASs) have identified novel diabetes-associated genes. We evaluated how these variants impact diabetes incidence, quantitative glycemic traits, and response to preventive interventions in 3,548 subjects at high risk of type 2 diabetes enrolled in the Diabetes Prevention Program (DPP), which examined the effects of lifestyle intervention, metformin, and troglitazone versus placebo. RESEARCH DESIGN AND METHODS— We genotyped selected single nucleotide polymorphisms (SNPs) in or near diabetes-associated loci, including EXT2, CDKAL1, CDKN2A/B, IGF2BP2, HHEX, LOC387761, and SLC30A8 in DPP participants and performed Cox regression analyses using genotype, intervention, and their interactions as predictors of diabetes incidence. We evaluated their effect on insulin resistance and secretion at 1 year. RESULTS— None of the selected SNPs were associated with increased diabetes incidence in this population. After adjustments for ethnicity, baseline insulin secretion was lower in subjects with the risk genotype at HHEX rs1111875 (P = 0.01); there were no significant differences in baseline insulin sensitivity. Both at baseline and at 1 year, subjects with the risk genotype at LOC387761 had paradoxically increased insulin secretion; adjustment for self-reported ethnicity abolished these differences. In ethnicity-adjusted analyses, we noted a nominal differential improvement in β-cell function for carriers of the protective genotype at CDKN2A/B after 1 year of troglitazone treatment (P = 0.01) and possibly lifestyle modification (P = 0.05). CONCLUSIONS— We were unable to replicate the GWAS findings regarding diabetes risk in the DPP. We did observe genotype associations with differences in baseline insulin secretion at the HHEX locus and a possible pharmacogenetic interaction at CDKNA2/B.

Published
2008

44. Common variants at CD40 and other loci confer risk of rheumatoid arthritis

Author

Robert M. Plenge, J. Bart A. Crusius, Niek de Vries, Soumya Raychaudhuri, Mark Seielstad, Tom W J Huizinga, Ann B. Begovich, Lars Klareskog, Peter K. Gregersen, Benjamin D. Korman, René E. M. Toes, Elizabeth W. Karlson, Annette Lee, Lindsey A. Criswell, Monica Chang, Candace Guiducci, Sandra Wong, Nancy A. Shadick, Karen H. Costenbader, Joseph J. Catanese, Michael F. Seldin, David Altshuler, Lauren Gianniny, Daniel L. Kastner, Elaine F. Remmers, Jane Worthington, Paul P. Tak, Annette H M van der Helm-van Mil, Michael E. Weinblatt, Kristin G. Ardlie, Jing Cui, Rachel Hackett, Fina A S Kurreeman, Gertjan Wolbink, Mark J. Daly, Benjamin M. Neale, Bo Ding, Irene E. van der Horst-Bruinsma, Jonathan S. Coblyn, Lars Alfredsson, Christopher I. Amos, Noël P. Burtt, Leonid Padyukov, Rheumatology, CCA - Disease profiling, Pathology, AII - Amsterdam institute for Infection and Immunity, Clinical Immunology and Rheumatology, and Landsteiner Laboratory

Subjects
PRKCQ, Genetic Linkage, Single-nucleotide polymorphism, Locus (genetics), Biology, TNFAIP3, Polymorphism, Single Nucleotide, Article, Arthritis, Rheumatoid, Genetic linkage, Genetics, medicine, Chromosomes, Human, Humans, Genetic Predisposition to Disease, CD40 Antigens, Gene, Genome, Human, Haplotype, Chromosome Mapping, medicine.disease, Haplotypes, Rheumatoid arthritis, Case-Control Studies, Immunology
Abstract

To identify rheumatoid arthritis risk loci in European populations, we conducted a meta-analysis of two published genome-wide association (GWA) studies totaling 3,393 cases and 12,462 controls. We genotyped 31 top-ranked SNPs not previously associated with rheumatoid arthritis in an independent replication of 3,929 autoantibody-positive rheumatoid arthritis cases and 5,807 matched controls from eight separate collections. We identified a common variant at the CD40 gene locus (rs4810485, P = 0.0032 replication, P = 8.2 x 10(-9) overall, OR = 0.87). Along with other associations near TRAF1 (refs. 2,3) and TNFAIP3 (refs. 4,5), this implies a central role for the CD40 signaling pathway in rheumatoid arthritis pathogenesis. We also identified association at the CCL21 gene locus (rs2812378, P = 0.00097 replication, P = 2.8 x 10(-7) overall), a gene involved in lymphocyte trafficking. Finally, we identified evidence of association at four additional gene loci: MMEL1-TNFRSF14 (rs3890745, P = 0.0035 replication, P = 1.1 x 10(-7) overall), CDK6 (rs42041, P = 0.010 replication, P = 4.0 x 10(-6) overall), PRKCQ (rs4750316, P = 0.0078 replication, P = 4.4 x 10(-6) overall), and KIF5A-PIP4K2C (rs1678542, P = 0.0026 replication, P = 8.8 x 10(-8) overall).

Published
2008

45. Testing of diabetes-associated WFS1 polymorphisms in the Diabetes Prevention Program

Author

Nicholas J. Wareham, Jarred B. McAteer, Manjinder S. Sandhu, Jose C. Florez, Paul W. Franks, Kathleen A. Jablonski, W. C. Knowler, Inês Barroso, and David Altshuler

Subjects
medicine.medical_specialty, endocrine system diseases, Wolfram syndrome, Endocrinology, Diabetes and Metabolism, Single-nucleotide polymorphism, Type 2 diabetes, Polymorphism, Single Nucleotide, Article, Linkage Disequilibrium, Atrophy, Internal medicine, Diabetes mellitus, Odds Ratio, Internal Medicine, medicine, Humans, Glucose tolerance test, medicine.diagnostic_test, Genome, Human, business.industry, Incidence (epidemiology), Membrane Proteins, nutritional and metabolic diseases, medicine.disease, Endocrinology, Diabetes Mellitus, Type 2, Diabetes insipidus, business
Abstract

Aims/hypothesis Wolfram syndrome (diabetes insipidus, diabetes mellitus, optic atrophy and deafness) is caused by mutations in the WFS1 gene. Recently, single nucleotide polymorphisms (SNPs) in WFS1 have been reproducibly associated with type 2 diabetes. We therefore examined the effects of these variants on diabetes incidence and response to interventions in the Diabetes Prevention Program (DPP), in which a lifestyle intervention or metformin treatment was compared with placebo.

Published
2007

46. Polymorphism at the TNF superfamily gene TNFSF4 confers susceptibility to systemic lupus erythematosus

Author

Timothy W. Behrens, Kathy L. Moser, Deborah S. Cunninghame Graham, Timothy J. Vyse, Patrick M. Gaffney, Andrew Wong, Harinder Manku, Robert R. Graham, David Altshuler, John C. Whittaker, and John D. Rioux

Subjects
medicine.medical_treatment, T cell, OX40 Ligand, Biology, Polymorphism, Single Nucleotide, Article, Genetics, medicine, Lupus Erythematosus, Systemic, Genetic Predisposition to Disease, Promoter Regions, Genetic, skin and connective tissue diseases, Receptor, Cells, Cultured, Autoimmune disease, Polymorphism, Genetic, Haplotype, FCGR3B, medicine.disease, United Kingdom, Cytokine, medicine.anatomical_structure, Haplotypes, Immunology, Tumor necrosis factor alpha, IRF5
Abstract

Systemic lupus erythematosus (SLE) is a multisystem complex autoimmune disease of uncertain etiology (OMIM 152700). Over recent years a genetic component to SLE susceptibility has been established1–3. Recent successes with association studies in SLE have identified genes including IRF5 (refs. 4,5) and FCGR3B6. Two tumor necrosis factor (TNF) superfamily members located within intervals showing genetic linkage with SLE are TNFSF4 (also known as OX40L; 1q25), which is expressed on activated antigen-presenting cells (APCs)7,8 and vascular endothelial cells9, and also its unique receptor, TNFRSF4 (also known as OX40; 1p36), which is primarily expressed on activated CD4+ T cells10. TNFSF4 produces a potent co-stimulatory signal for activated CD4+ T cells after engagement of TNFRSF4 (ref. 11). Using both a family-based and a case-control study design, we show that the upstream region of TNFSF4 contains a single risk haplotype for SLE, which is correlated with increased expression of both cell-surface TNFSF4 and the TNFSF4 transcript. We hypothesize that increased expression of TNFSF4 predisposes to SLE either by quantitatively augmenting T cell–APC interaction or by influencing the functional consequences of T cell activation via TNFRSF4.

Published
2007

47. Haplotypes of the estrogen receptor beta gene and breast cancer risk

Author

Laurence N. Kolonel, Dimitrios Trichopoulos, Göran Berglund, Meredith Yeager, Pilar Amiano, Noël P. Burtt, Philip Bretsky, Anne Tjønneland, Christopher A. Haiman, Stephen J. Chanock, Malcolm Cecil Pike, Julie E. Buring, Ruth C. Travis, Michael J. Thun, Graham A. Colditz, Domenico Palli, Joel N. Hirschhorn, Brian E. Henderson, David G. Cox, Elio Riboli, Federico Canzian, Robert N. Hoover, Heiner Boeing, Eiliv Lund, Heather Spencer Feigelson, Françoise Clavel-Chapelon, David Altshuler, Daniel O. Stram, David J. Hunter, Petra H.M. Peeters, Rudolf Kaaks, Paul D.P. Pharoah, Peter Kraft, Demetrius Albanes, Loic LeMarchand, Eugenia E. Calle, and Susan E. Hankinson

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Cancer prevention, business.industry, Haplotype, Cancer, Estrogen receptor, medicine.disease, European Prospective Investigation into Cancer and Nutrition, Prostate cancer, Endocrinology, Breast cancer, Internal medicine, medicine, business, Estrogen receptor beta
Abstract

Exposure to exogenous (oral contraceptives, postmenopausal hormone therapy) and endogenous (number of ovulatory cycles, adiposity) steroid hormones is associated with breast cancer risk. Breast cancer risk associated with these exposures could hypothetically be modified by genes in the steroid hormone synthesis, metabolism and signaling pathways. Estrogen receptors are the first step along the path of signaling cell growth and development upon stimulation with estrogens. The National Cancer Institute Breast and Prostate Cancer Cohort Consortium has systematically selected haplotype tagging SNPs in genes along the steroid hormone synthesis, metabolism and binding pathways, including the estrogen receptor beta (ESR2) gene. Four htSNPs tag the 6 major (>5% frequency) haplotypes of the ESR2 gene. These polymorphisms have been genotyped in 5,789 breast cancer cases and 7,761 controls nested within the American Cancer Society Cancer Prevention Study II, European Prospective Investigation into Cancer and Nutrition, Multiethnic Cohort, Nurses' Health Study and Women's Health Study cohorts. None of the SNPs were independently associated with breast cancer risk. One haplotype of the ESR2 gene was associated with breast cancer risk before correction for multiple testing (OR 1.17, 95% CI 1.07-1.28, p = 0.0007). This haplotype remained associated with breast cancer risk after adjustment for multiple testing using a permutation procedure. There was no statistically significant heterogeneity in SNP or haplotype odds ratios across cohorts. These data suggest that inherited variants in ESR2 (while possibly conferring a small increased risk of breast cancer) are not associated with appreciable (OR > 1.2) changes in breast cancer risk among Caucasian women.

Published
2007

48. Genetic and functional analysis ofCHEK2 (CHK2) variants in multiethnic cohorts

Author

Mary B. Daly, Kristin B. Niendorf, Dennis C. Sgroi, Brian E. Henderson, Daniel A. Haber, Doke C.R. Wahrer, Patricia L. Harris, Christopher A. Haiman, Sara M. Haserlat, Sang H. Kim, Judy Garber, Matthew L. Freedman, Loic Le Marchand, Olufunmilayo I. Olopade, David Altshuler, Daphne W. Bell, Matthew R. Smith, Andrew K. Godwin, and Taryn A. Schiripo

Subjects
Male, Threonine, Cancer Research, DNA Mutational Analysis, Gene Frequency, Risk Factors, Missense mutation, Age of Onset, skin and connective tissue diseases, Genetics, education.field_of_study, Hispanic or Latino, Middle Aged, Oncology, Protein destabilization, Female, Adult, DNA, Complementary, Proline, Population, Mutation, Missense, Breast Neoplasms, Protein Serine-Threonine Kinases, Risk Assessment, Article, Hawaii, White People, Breast cancer, Germline mutation, Asian People, Leucine, Predictive Value of Tests, medicine, Humans, Genetic Predisposition to Disease, Histidine, Isoleucine, Risk factor, education, CHEK2, Germ-Line Mutation, Aged, business.industry, Prostatic Neoplasms, Cancer, medicine.disease, United States, Black or African American, Checkpoint Kinase 2, Case-Control Studies, Mutation, Tyrosine, business
Abstract

The CHEK2-1100delC mutation is recurrent in the population and is a moderate risk factor for breast cancer. To identify additional CHEK2 mutations potentially contributing to breast cancer susceptibility, we sequenced 248 cases with early-onset disease; functionally characterized new variants and conducted a population-based case-control analysis to evaluate their contribution to breast cancer risk. We identified 1 additional null mutation and 5 missense variants in the germline of cancer patients. In vitro, the CHEK2-H143Y variant resulted in gross protein destabilization, while others had variable suppression of in vitro kinase activity using BRCA1 as a substrate. The germline CHEK2-1100delC mutation was present among 8/1,646 (0.5%) sporadic, 2/400 (0.5%) early-onset and 3/302 (1%) familial breast cancer cases, but undetectable amongst 2,105 multiethnic controls, including 633 from the US. CHEK2-positive breast cancer families also carried a deleterious BRCA1 mutation. 1100delC appears to be the only recurrent CHEK2 mutation associated with a potentially significant contribution to breast cancer risk in the general population. Another recurrent mutation with attenuated in vitro function, CHEK2-P85L, is not associated with increased breast cancer susceptibility, but exhibits a striking difference in frequency across populations with different ancestral histories. These observations illustrate the importance of genotyping ethnically diverse groups when assessing the impact of low-penetrance susceptibility alleles on population risk. Our findings highlight the notion that clinical testing for rare missense mutations within CHEK2 may have limited value in predicting breast cancer risk, but that testing for the 1100delC variant may be valuable in phenotypically- and geographically-selected populations.

Published
2007

49. Rare variant associations with waist-to-hip ratio in European-American and African-American women from the NHLBI-Exome Sequencing Project

Author

Jaclyn Ellis, Kari E. North, Yii-Der Ida Chen, Myron D. Gross, Christopher S. Carlson, Biao Li, Gao Wang, Li Hsu, Leslie A. Lange, Stacey Gabriel, Gonçalo R. Abecasis, Nora Franceschini, Paul L. Auer, Deborah A. Nickerson, Danyu Lin, James S. Pankow, Kristine L. Bucasas, Ulrike Peters, Alexander P. Reiner, Joshua D. Smith, Josée Dupuis, L. Adrienne Cupples, Suzanne M. Leal, Stanley Hooker, James G. Wilson, David S. Siscovick, Caroline S. Fox, James B. Meigs, David Altshuler, Mengyuan Kan, Jay Shendure, Rebecca D. Jackson, Hua Zhong, Alejandra Rodriguez, Michael J. Bamshad, Jerome I. Rotter, and Nancy L. Heard-Costa

Subjects
0301 basic medicine, Adult, Waist, IKBKB Gene, 030209 endocrinology & metabolism, Type 2 diabetes, Biology, White People, Article, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, Waist–hip ratio, Genetics, medicine, Humans, Exome, Genetics (clinical), Exome sequencing, Alleles, Genetic association, Aged, Aged, 80 and over, Polymorphism, Genetic, Waist-Hip Ratio, Middle Aged, medicine.disease, I-kappa B Kinase, Black or African American, 030104 developmental biology, Female, Transcription Factors
Abstract

Waist-to-hip ratio (WHR), a relative comparison of waist and hip circumferences, is an easily accessible measurement of body fat distribution, in particular central abdominal fat. A high WHR indicates more intra-abdominal fat deposition and is an established risk factor for cardiovascular disease and type 2 diabetes. Recent genome-wide association studies have identified numerous common genetic loci influencing WHR, but the contributions of rare variants have not been previously reported. We investigated rare variant associations with WHR in 1510 European-American and 1186 African-American women from the National Heart, Lung, and Blood Institute-Exome Sequencing Project. Association analysis was performed on the gene level using several rare variant association methods. The strongest association was observed for rare variants in IKBKB (P=4.0 × 10(-8)) in European-Americans, where rare variants in this gene are predicted to decrease WHRs. The activation of the IKBKB gene is involved in inflammatory processes and insulin resistance, which may affect normal food intake and body weight and shape. Meanwhile, aggregation of rare variants in COBLL1, previously found to harbor common variants associated with WHR and fasting insulin, were nominally associated (P=2.23 × 10(-4)) with higher WHR in European-Americans. However, these significant results are not shared between African-Americans and European-Americans that may be due to differences in the allelic architecture of the two populations and the small sample sizes. Our study indicates that the combined effect of rare variants contribute to the inter-individual variation in fat distribution through the regulation of insulin response.

Published
2015

50. Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease

Author

Anne Keogh, Sanjay K Prasad, Jason Flannick, Diane Fatkin, Magdi H. Yacoub, Antonio de Marvao, David Altshuler, Francesco Mazzarotto, Peter S. Macdonald, Daniel S. Herman, Jonathan G. Seidman, Sebastian Schafer, Michael Gotthardt, Leanne E. Felkin, Rachel Buchan, Ankur Gulati, Christopher J. O'Donnell, Stuart A. Cook, Michael H. Radke, Jacqueline A. L. MacArthur, Christine E. Seidman, Dudley J. Pennell, James G. Wilson, Christopher S. Hayward, John Baksi, Sungsam Gong, S Wilkinson, James S. Ware, Timothy J W Dawes, Fiona Cunningham, Nicholas R. Banner, Norbert Hubner, Shibu John, Paul J.R. Barton, Stacey Gabriel, Roddy Walsh, Matthias Heinig, Declan P. O'Regan, Tan Ru San, Angharad M. Roberts, Alexander G. Bick, Emma J. Birks, British Heart Foundation, Heart Research UK, and Commission of the European Communities

Subjects
Transcription, Genetic, Cardiomyopathy, FAMILIAL DILATED CARDIOMYOPATHY, Disease, Research & Experimental Medicine, VARIANTS, Transcriptome, Cohort Studies, Protein Isoforms, Connectin, 10. No inequality, POPULATION, 11 Medical and Health Sciences, Genetics, education.field_of_study, biology, Dilated cardiomyopathy, Heart, General Medicine, Exons, Middle Aged, Penetrance, Healthy Volunteers, 3. Good health, PROGNOSTIC VALUE, Medicine, Research & Experimental, CARDIOVASCULAR MAGNETIC-RESONANCE, HEART-FAILURE, Titin, Life Sciences & Biomedicine, Adult, Cardiomyopathy, Dilated, GENES, Adolescent, Population, Immunoglobulins, Computational biology, SEQUENCE, Young Adult, medicine, Humans, Allele, education, Alleles, Aged, Heart Failure, Science & Technology, MUTATIONS, Genetic Variation, Cell Biology, 06 Biological Sciences, medicine.disease, Mutation, RISK-FACTORS, biology.protein
Abstract

The recent discovery of heterozygous human mutations that truncate full-length titin (TTN, an abundant structural, sensory, and signaling filament in muscle) as a common cause of end-stage dilated cardiomyopathy (DCM) promises new prospects for improving heart failure management. However, realization of this opportunity has been hindered by the burden of TTN-truncating variants (TTNtv) in the general population and uncertainty about their consequences in health or disease. To elucidate the effects of TTNtv, we coupled TTN gene sequencing with cardiac phenotyping in 5267 individuals across the spectrum of cardiac physiology and integrated these data with RNA and protein analyses of human heart tissues. We report diversity of TTN isoform expression in the heart, define the relative inclusion of TTN exons in different isoforms (using the TTN transcript annotations available at http://cardiodb.org/titin), and demonstrate that these data, coupled with the position of the TTNtv, provide a robust strategy to discriminate pathogenic from benign TTNtv. We show that TTNtv is the most common genetic cause of DCM in ambulant patients in the community, identify clinically important manifestations of TTNtv-positive DCM, and define the penetrance and outcomes of TTNtv in the general population. By integrating genetic, transcriptome, and protein analyses, we provide evidence for a length-dependent mechanism of disease. These data inform diagnostic criteria and management strategies for TTNtv-positive DCM patients and for TTNtv that are identified as incidental findings.

Published
2015

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