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14 results on '"Efthymia Vlachopoulou"'

1. Genome-Wide Association Study of Peripheral Artery Disease

Author

Natalie R. van Zuydam, Alexander Stiby, Moustafa Abdalla, Erin Austin, Emma H. Dahlström, Stela McLachlan, Efthymia Vlachopoulou, Emma Ahlqvist, Chen Di Liao, Niina Sandholm, Carol Forsblom, Anubha Mahajan, Neil R. Robertson, N. William Rayner, Eero Lindholm, Juha Sinisalo, Markus Perola, Milla Kallio, Emily Weiss, Jackie Price, Andrew Paterson, Barbara Klein, Veikko Salomaa, Colin N.A. Palmer, Per-Henrik Groop, Leif Groop, Mark I. McCarthy, Mariza de Andrade, Andrew P. Morris, Jemma C. Hopewell, Helen M. Colhoun, Iftikhar J. Kullo, Sólveig Grétarsdóttir, Guðmar Þorleifsson, Unnur þorsteinsdóttir, Kari Stefansson, Michael Mark, Timo Kanninen, Barbara Thorand, Giuseppe Remuzzi, David Dunger, Angela Shore, Ulf Smith, Seppo Ylä-Herttuala, Claudio Cobelli, Riccardo Bellazzi, Ele Ferrannini, Carlo Patrono, Pirjo Nuutila, Paul McKeague, Birgit Steckel-Hamann, Li-ming Gan, Everson Nogoceke, Piero Tortoli, Bernd Jablonka, Mary-Julia Brosnan, Consortium, GoLEAD, Consortium, SUMMIT, HUS Internal Medicine and Rehabilitation, HUS Abdominal Center, Nefrologian yksikkö, CAMM - Research Program for Clinical and Molecular Metabolism, Department of Medicine, Helsinki University Hospital Area, Clinicum, Medicum, Research Programs Unit, HUS Heart and Lung Center, Institute for Molecular Medicine Finland, Verisuonikirurgian yksikkö, Per Henrik Groop / Principal Investigator, Centre of Excellence in Complex Disease Genetics, and Leif Groop Research Group

Subjects
Male, LD SCORE REGRESSION, Genome-wide association study, Disease, 030204 cardiovascular system & hematology, 0302 clinical medicine, Stroke, 0303 health sciences, diabetes, 1184 Genetics, developmental biology, physiology, General Medicine, 3. Good health, PREVALENCE, INSIGHTS, peripheral vascular disease, Endokrinologi och diabetes, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Medical genetics, Diabetes, Genome-wide Association Study, Peripheral Vascular Disease, Smoking, Female, Medical Genetics, STROKE, PROVIDES, medicine.medical_specialty, DATABASE, PATHOPHYSIOLOGY, Context (language use), Endocrinology and Diabetes, Polymorphism, Single Nucleotide, smoking, 03 medical and health sciences, Peripheral Arterial Disease, Diabetes mellitus, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, 030304 developmental biology, Genetic association, Medicinsk genetik, genome-wide association study, business.industry, Odds ratio, Original Articles, medicine.disease, NICOTINE DEPENDENCE, 3121 General medicine, internal medicine and other clinical medicine, RISK-FACTORS, business
Abstract

Supplemental Digital Content is available in the text., Background: Peripheral artery disease (PAD) affects >200 million people worldwide and is associated with high mortality and morbidity. We sought to identify genomic variants associated with PAD overall and in the contexts of diabetes and smoking status. Methods: We identified genetic variants associated with PAD and then meta-analyzed with published summary statistics from the Million Veterans Program and UK Biobank to replicate their findings. Next, we ran stratified genome-wide association analysis in ever smokers, never smokers, individuals with diabetes, and individuals with no history of diabetes and corresponding interaction analyses, to identify variants that modify the risk of PAD by diabetic or smoking status. Results: We identified 5 genome-wide significant (Passociation ≤5×10−8) associations with PAD in 449 548 (Ncases=12 086) individuals of European ancestry near LPA (lipoprotein [a]), CDKN2BAS1 (CDKN2B antisense RNA 1), SH2B3 (SH2B adaptor protein 3) - PTPN11 (protein tyrosine phosphatase non-receptor type 11), HDAC9 (histone deacetylase 9), and CHRNA3 (cholinergic receptor nicotinic alpha 3 subunit) loci (which overlapped previously reported associations). Meta-analysis with variants previously associated with PAD showed that 18 of 19 published variants remained genome-wide significant. In individuals with diabetes, rs116405693 at the CCSER1 (coiled-coil serine rich protein 1) locus was associated with PAD (odds ratio [95% CI], 1.51 [1.32–1.74], Pdiabetes=2.5×10−9, Pinteractionwithdiabetes=5.3×10−7). Furthermore, in smokers, rs12910984 at the CHRNA3 locus was associated with PAD (odds ratio [95% CI], 1.15 [1.11–1.19], Psmokers=9.3×10−10, Pinteractionwithsmoking=3.9×10−5). Conclusions: Our analyses confirm the published genetic associations with PAD and identify novel variants that may influence susceptibility to PAD in the context of diabetes or smoking status.

Published
2021

2. Genetic predisposition to coronary artery disease in type 2 diabetes mellitus

Author

Natalie R. van Zuydam, Claes Ladenvall, Benjamin F. Voight, Rona J. Strawbridge, Juan Fernandez-Tajes, N. William Rayner, Neil R. Robertson, Anubha Mahajan, Efthymia Vlachopoulou, Anuj Goel, Marcus E. Kleber, Christopher P. Nelson, Lydia Coulter Kwee, Tõnu Esko, Evelin Mihailov, Reedik Mägi, Lili Milani, Krista Fischer, Stavroula Kanoni, Jitender Kumar, Ci Song, Jaana A. Hartiala, Nancy L. Pedersen, Markus Perola, Christian Gieger, Annette Peters, Liming Qu, Sara M. Willems, Alex S.F. Doney, Andrew D. Morris, Yan Zheng, Giorgio Sesti, Frank B. Hu, Lu Qi, Markku Laakso, Unnur Thorsteinsdottir, Harald Grallert, Cornelia van Duijn, Muredach P. Reilly, Erik Ingelsson, Panos Deloukas, Sek Kathiresan, Andres Metspalu, Svati H. Shah, Juha Sinisalo, Veikko Salomaa, Anders Hamsten, Nilesh J. Samani, Winfried März, Stanley L. Hazen, Hugh Watkins, Danish Saleheen, Andrew P. Morris, Helen M. Colhoun, Leif Groop, Mark I. McCarthy, Colin N.A. Palmer, John Danesh, Jeanette Erdmann, Dongfeng Gu, Jaspal S. Kooner, Robert Roberts, Heribert Schunkert, Themistocles L. Assimes, Stefan Blankenberg, Bernhard O. Boehm, John C. Chambers, Robert Clarke, Rory Collins, George Dedoussis, Paul W. Franks, G. Kees Hovingh, Bong-Jo Kim, Terho Lehtimäki, Ruth McPherson, Markku S Nieminen, Christopher O’Donnell, Samuli Ripatti, Manjinder S Sandhu, Stefan Schreiber, Agneta Siegbahn, Cristen J. Willer, Pierre A. Zalloua, Michael Mark, Timo Kanninen, Barbara Thorand, Giuseppe Remuzzi, David Dunger, Angela Shore, Ulf Smith, Per-Henrik Groop, Seppo Ylä-Herttuala, Claudio Cobelli, Riccardo Bellazzi, Ele Ferrannini, Carlo Patrono, Pirjo Nuutila, Paul McKeague, Birgit Steckel-Hamann, Li-ming Gan, Everson Nogoceke, Piero Tortoli, Bernd Jablonka, Mary-Julia Brosnan, Tampere University, Department of Clinical Chemistry, Clinical Medicine, Transplantation Laboratory, University of Helsinki, Research Programs Unit, CAMM - Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, Department of Medicine, Doctoral Programme in Clinical Research, Clinicum, HUS Heart and Lung Center, Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institute for Molecular Medicine Finland, Department of Public Health, Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, University Management, Biostatistics Helsinki, and Epidemiology

Subjects
0301 basic medicine, Heart disease, endocrine system diseases, LOCI, Genome-wide association study, CAD, 030204 cardiovascular system & hematology, GLUCOSE, Coronary artery disease, 0302 clinical medicine, risk factors, blood pressure, coronary artery disease, diabetes mellitus, genome-wide association study, RISK, 1184 Genetics, developmental biology, physiology, COMMON VARIANTS, General Medicine, INSIGHTS, CARDIOVASCULAR-DISEASE, Cardiology, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Medical genetics, Medical Genetics, medicine.medical_specialty, endocrine system, Blood Pressure, Coronary Artery Disease, Diabetes Mellitus, Genome-wide Association Study, Risk Factors, HEART-DISEASE, 3121 Internal medicine, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Meta-Analysis as Topic, Internal medicine, Genetic predisposition, medicine, GLYCEMIC TRAITS, Humans, Genetic Predisposition to Disease, cardiovascular diseases, GENOME-WIDE ASSOCIATION, Medicinsk genetik, Polymorphism, Genetic, business.industry, Type 2 Diabetes Mellitus, PATHWAYS, nutritional and metabolic diseases, Original Articles, medicine.disease, Genetic architecture, 030104 developmental biology, Diabetes Mellitus, Type 2, Case-Control Studies, 3121 General medicine, internal medicine and other clinical medicine, 3111 Biomedicine, business, human activities
Abstract

Supplemental Digital Content is available in the text., Background: Coronary artery disease (CAD) is accelerated in subjects with type 2 diabetes mellitus (T2D). Methods: To test whether this reflects differential genetic influences on CAD risk in subjects with T2D, we performed a systematic assessment of genetic overlap between CAD and T2D in 66 643 subjects (27 708 with CAD and 24 259 with T2D). Variants showing apparent association with CAD in stratified analyses or evidence of interaction were evaluated in a further 117 787 subjects (16 694 with CAD and 11 537 with T2D). Results: None of the previously characterized CAD loci was found to have specific effects on CAD in T2D individuals, and a genome-wide interaction analysis found no new variants for CAD that could be considered T2D specific. When we considered the overall genetic correlations between CAD and its risk factors, we found no substantial differences in these relationships by T2D background. Conclusions: This study found no evidence that the genetic architecture of CAD differs in those with T2D compared with those without T2D.

Published
2020

3. Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders

Author

Symen Ligthart, Ahmad Vaez, Urmo Võsa, Maria G. Stathopoulou, Paul S. de Vries, Bram P. Prins, Peter J. Van der Most, Toshiko Tanaka, Elnaz Naderi, Lynda M. Rose, Ying Wu, Robert Karlsson, Maja Barbalic, Honghuang Lin, René Pool, Gu Zhu, Aurélien Macé, Carlo Sidore, Stella Trompet, Massimo Mangino, Maria Sabater-Lleal, John P. Kemp, Ali Abbasi, Tim Kacprowski, Niek Verweij, Albert V. Smith, Tao Huang, Carola Marzi, Mary F. Feitosa, Kurt K. Lohman, Marcus E. Kleber, Yuri Milaneschi, Christian Mueller, Mahmudul Huq, Efthymia Vlachopoulou, Leo-Pekka Lyytikäinen, Christopher Oldmeadow, Joris Deelen, Markus Perola, Jing Hua Zhao, Bjarke Feenstra, Marzyeh Amini, Jari Lahti, Katharina E. Schraut, Myriam Fornage, Bhoom Suktitipat, Wei-Min Chen, Xiaohui Li, Teresa Nutile, Giovanni Malerba, Jian’an Luan, Tom Bak, Nicholas Schork, Fabiola Del Greco M., Elisabeth Thiering, Anubha Mahajan, Riccardo E. Marioni, Evelin Mihailov, Joel Eriksson, Ayse Bilge Ozel, Weihua Zhang, Maria Nethander, Yu-Ching Cheng, Stella Aslibekyan, Wei Ang, Ilaria Gandin, Loïc Yengo, Laura Portas, Charles Kooperberg, Edith Hofer, Kumar B. Rajan, Claudia Schurmann, Wouter den Hollander, Tarunveer S. Ahluwalia, Jing Zhao, Harmen H.M. Draisma, Ian Ford, Nicholas Timpson, Alexander Teumer, Hongyan Huang, Simone Wahl, YongMei Liu, Jie Huang, Hae-Won Uh, Frank Geller, Peter K. Joshi, Lisa R. Yanek, Elisabetta Trabetti, Benjamin Lehne, Diego Vozzi, Marie Verbanck, Ginevra Biino, Yasaman Saba, Ingrid Meulenbelt, Jeff R. O’Connell, Markku Laakso, Franco Giulianini, Patrik K.E. Magnusson, Christie M. Ballantyne, Jouke Jan Hottenga, Grant W. Montgomery, Fernando Rivadineira, Rico Rueedi, Maristella Steri, Karl-Heinz Herzig, David J. Stott, Cristina Menni, Mattias Frånberg, Beate St. Pourcain, Stephan B. Felix, Tune H. Pers, Stephan J.L. Bakker, Peter Kraft, Annette Peters, Dhananjay Vaidya, Graciela Delgado, Johannes H. Smit, Vera Großmann, Juha Sinisalo, Ilkka Seppälä, Stephen R. Williams, Elizabeth G. Holliday, Matthijs Moed, Claudia Langenberg, Katri Räikkönen, Jingzhong Ding, Harry Campbell, Michele M. Sale, Yii-Der I. Chen, Alan L. James, Daniela Ruggiero, Nicole Soranzo, Catharina A. Hartman, Erin N. Smith, Gerald S. Berenson, Christian Fuchsberger, Dena Hernandez, Carla M.T. Tiesler, Vilmantas Giedraitis, David Liewald, Krista Fischer, Dan Mellström, Anders Larsson, Yunmei Wang, William R. Scott, Matthias Lorentzon, John Beilby, Kathleen A. Ryan, Craig E. Pennell, Dragana Vuckovic, Beverly Balkau, Maria Pina Concas, Reinhold Schmidt, Carlos F. Mendes de Leon, Erwin P. Bottinger, Margreet Kloppenburg, Lavinia Paternoster, Michael Boehnke, A.W. Musk, Gonneke Willemsen, David M. Evans, Pamela A.F. Madden, Mika Kähönen, Zoltán Kutalik, Magdalena Zoledziewska, Ville Karhunen, Stephen B. Kritchevsky, Naveed Sattar, Genevieve Lachance, Robert Clarke, Tamara B. Harris, Olli T. Raitakari, John R. Attia, Diana van Heemst, Eero Kajantie, Rossella Sorice, Giovanni Gambaro, Robert A. Scott, Andrew A. Hicks, Luigi Ferrucci, Marie Standl, Cecilia M. Lindgren, John M. Starr, Magnus Karlsson, Lars Lind, Jun Z. Li, John C. Chambers, Trevor A. Mori, Eco J.C.N. de Geus, Andrew C. Heath, Nicholas G. Martin, Juha Auvinen, Brendan M. Buckley, Anton J.M. de Craen, Melanie Waldenberger, Konstantin Strauch, Thomas Meitinger, Rodney J. Scott, Mark McEvoy, Marian Beekman, Cristina Bombieri, Paul M. Ridker, Karen L. Mohlke, Nancy L. Pedersen, Alanna C. Morrison, Dorret I. Boomsma, John B. Whitfield, David P. Strachan, Albert Hofman, Peter Vollenweider, Francesco Cucca, Marjo-Riitta Jarvelin, J. Wouter Jukema, Tim D. Spector, Anders Hamsten, Tanja Zeller, André G. Uitterlinden, Matthias Nauck, Vilmundur Gudnason, Lu Qi, Harald Grallert, Ingrid B. Borecki, Jerome I. Rotter, Winfried März, Philipp S. Wild, Marja-Liisa Lokki, Michael Boyle, Veikko Salomaa, Mads Melbye, Johan G. Eriksson, James F. Wilson, Brenda W.J.H. Penninx, Diane M. Becker, Bradford B. Worrall, Greg Gibson, Ronald M. Krauss, Marina Ciullo, Gianluigi Zaza, Nicholas J. Wareham, Albertine J. Oldehinkel, Lyle J. Palmer, Sarah S. Murray, Peter P. Pramstaller, Stefania Bandinelli, Joachim Heinrich, Erik Ingelsson, Ian J. Deary, Reedik Mägi, Liesbeth Vandenput, Pim van der Harst, Karl C. Desch, Jaspal S. Kooner, Claes Ohlsson, Caroline Hayward, Terho Lehtimäki, Alan R. Shuldiner, Donna K. Arnett, Lawrence J. Beilin, Antonietta Robino, Philippe Froguel, Mario Pirastu, Tine Jess, Wolfgang Koenig, Ruth J.F. Loos, Denis A. Evans, Helena Schmidt, George Davey Smith, P. Eline Slagboom, Gudny Eiriksdottir, Andrew P. Morris, Bruce M. Psaty, Russell P. Tracy, Ilja M. Nolte, Eric Boerwinkle, Sophie Visvikis-Siest, Alex P. Reiner, Myron Gross, Joshua C. Bis, Lude Franke, Oscar H. Franco, Emelia J. Benjamin, Daniel I. Chasman, Josée Dupuis, Harold Snieder, Abbas Dehghan, Behrooz Z. Alizadeh, H. Marike Boezen, Gerjan Navis, Marianne Rots, Morris Swertz, Bruce H.R. Wolffenbuttel, Cisca Wijmenga, Emelia Benjamin, Tarunveer Singh Ahluwalia, James Meigs, Russell Tracy, Josh Bis, Nathan Pankratz, Alex Rainer, James G. Wilson, Josee Dupuis, Bram Prins, Urmo Vaso, Maria Stathopoulou, Terho Lehtimaki, Yalda Jamshidi, Sophie Siest, Andre G. Uitterlinden, Mohammadreza Abdollahi, Renate Schnabel, Ursula M. Schick, Aldi Kraja, Yi-Hsiang Hsu, Daniel S. Tylee, Alyson Zwicker, Rudolf Uher, George Davey-Smith, Andrew Hicks, Cornelia M. van Duijn, Cavin Ward-Caviness, J. Rotter, Ken Rice, Leslie Lange, Eco de Geus, Kari Matti Makela, David Stacey, Johan Eriksson, Tim M. Frayling, Eline P. Slagboom, Erasmus University Medical Center [Rotterdam] (Erasmus MC), University Medical Center Groningen [Groningen] (UMCG), University of Isfahan, University of Tartu, Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), The University of Texas Health Science Center at Houston (UTHealth), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Brigham and Women's Hospital [Boston], University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], University of Split, Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Process & Energy Laboratory, Delft University of Technology (TU Delft), Grand Lyon : communauté urbaine de Lyon, Interuniversity Cardiology Institute Netherlands, Department of Twin Research and Genetic Epidemiology, King's College London, London, Huazhong University of Science and Technology [Wuhan] (HUST), Division of Statistical Genomics, Washington University School of Medicine, Department of Psychiatry, VU University Medical Center [Amsterdam], Institut fuer Theoretische Physik (Institut fuer Theoretische Physik), Universität Heidelberg [Heidelberg] = Heidelberg University, Molecular Epidemiology, MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Mahidol University [Bangkok], Northwest A and F University, Laboratoire d'Optimisation des Systèmes Industriels (LOSI), Institut Charles Delaunay (ICD), Université de Technologie de Troyes (UTT)-Centre National de la Recherche Scientifique (CNRS)-Université de Technologie de Troyes (UTT)-Centre National de la Recherche Scientifique (CNRS), Institute of Genetics and Biophysics, CNR, Naples, Università degli studi di Verona = University of Verona (UNIVR), Department of Molecular Medicine [Scripps Research Institute], The Scripps Research Institute [La Jolla, San Diego], Department of Physics, Indian Institute of Technology Kanpur (IIT Kanpur), Deptartment of Medical Biochemistry and Microbiology, Uppsala University, Department of Electrical and Computer Engineering [Waterloo] (ECE), University of Waterloo [Waterloo], University of Maryland School of Medicine, University of Maryland System, Institut National de l'Environnement Industriel et des Risques (INERIS), Institute of Pop. Genetics, CNR, Sassari, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, IT University of Copenhagen (ITU), Robertson Centre for Biostatistics, University of Glasgow, Centre for Causal Analyses in Translational Epidemiology, University of Bristol [Bristol]-Medical Research Council, King‘s College London, Jinan University [Guangzhou], Institute of Oceanology [China], School Medicine, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), General Internal Medicine, Johns Hopkins School of Medicine, Johns Hopkins University School of Medicine [Baltimore], Shardna life science Pula Cagliari, Section Molecular Epidemiology, Leiden University Medical Center (LUMC), Department of Medicine, University of Eastern Finland-Kuopio University Hospital, Medstar Research Institute, Department of Cardiology, Ernst-Moritz-Arndt University, Center for Biological Sequence Analysis [Lyngby], Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Department of Internal Medicine, University of Groningen and University Medical Center Groningen, Department of Epidemiology, Harvard School of Public Health, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Metacohorts Consortium, INEOS Technologies (SWITZERLAND), MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, University of Edinburgh, School of Population Health [Crawley, Western Australia], The University of Western Australia (UWA), Institute of Genetics and Biophysics, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), The Scripps Translational Science Institute and Scripps Health, Tulane Center for Cardiovascular Health, Tulane University Health Sciences Center, Centre for Population Health Sciences, Genomic Research Laboratory, Service of Infectious Disease, Hôpitaux Universitaires de Genève (HUG), Infectious diseases division, Department of internal medicine, Washington University in Saint Louis (WUSTL), Luleå University of Technology (LUT), Recherche en épidémiologie et biostatistique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Austrian Institute of Technology [Vienna] (AIT), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Department of Rheumatology and Clinical Epidemiology, Leiden University Medical Center (LUMC), Department of Rheumatology and Clinical Epidemiology [Leiden University Medical Center] (LUMC), Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden-Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, University of Virginia, Tampere University Hospital, Department of Medical Genetics, Université de Lausanne = University of Lausanne (UNIL), Department of Pathological Biochemistry, Royal Infirmary, Oxford University, University of Oxford, University of Newcastle [Callaghan, Australia] (UoN), Department of neurology, Institute of Metabolic Science, MRC, The Wellcome Trust Centre for Human Genetics [Oxford], Uppsala Universitet [Uppsala], QIMR Berghofer Medical Research Institute, Institute of Genetic Epidemiology [Neuherberg, Germany], Institute of Human Genetics, Helmholtz Zentrum München = German Research Center for Environmental Health, Schizophrenia Research Institute [Sydney], Department of Genetics, University of North Carolina System (UNC)-University of North Carolina System (UNC), Vrije Universiteit Brussel (VUB), Population Health Sciences and Education, St George's University of London, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Institute of Health Sciences and Biocenter Oulu, University of Oulu, Medizinische Klinik und Poliklinik, Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Institute of Clinical Chemistry and Laboratory Medicine, Icelandic Heart Association, Heart Preventive Clinic and Research Institute, Departments of Epidemiology and Nutrition, Institute of Epidemiology [Neuherberg] (EPI), Medical University Graz, Transplantation Laboratory [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Department of Chronic Disease Prevention, National Institute for Health and Welfare [Helsinki], Dept. of Epidemiology Research, Statens Serum Institut [Copenhagen], CLinical Psychology, Genetics and Pathology, Geriatric Rehabilitation Unit, Azienda Sanitaria Firenze, Center For Narcolepsy, Stanford University, Centre for Bone and Arthritis Research, University of Gothenburg (GU)-Institute of Medicine, MRC Human Gentics Unit, Inst Genet and Mol Med, Western General Hospital, Edinburgh, University of Maryland School of Medicine [Baltimore, MD, USA], Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Department of Physics [Stockholm], Stockholm University, University of Bristol [Bristol], Universiteit Leiden, Department of Epidemiology, University of Washington, University of Washington [Seattle], Department of Epidemiology [Rotterdam], University of Groningen [Groningen], Dutch Initiative on Crohn and Colitis (ICC), Icelandic Heart Association [Kopavogur, Iceland] (IHA), Department of Physiology and Biophysics [Jackson, MS, USA], University of Southern Mississippi (USM), Human Genetics Branch, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health (NIMH), Faculty of Medicine and Life Sciences [Tampere], University of Tampere [Finland], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council-Cardiff University, Department of Social Medicine, School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Department of Medicine [Aurora, CO, USA], University of Colorado [Denver], Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Mathematical Institute [Oxford] (MI), Institute of Psychiatry, Psychology & Neuroscience, King's College London, LifeLines Cohort Study, CHARGE Inflammation Working Group, Ligthart, S., Vaez, A., Vosa, U., Stathopoulou, M. G., de Vries, P. S., Prins, B. P., Van der Most, P. J., Tanaka, T., Naderi, E., Rose, L. M., Wu, Y., Karlsson, R., Barbalic, M., Lin, H., Pool, R., Zhu, G., Mace, A., Sidore, C., Trompet, S., Mangino, M., Sabater-Lleal, M., Kemp, J. P., Abbasi, A., Kacprowski, T., Verweij, N., Smith, A. V., Huang, T., Marzi, C., Feitosa, M. F., Lohman, K. K., Kleber, M. E., Milaneschi, Y., Mueller, C., Huq, M., Vlachopoulou, E., Lyytikainen, L. -P., Oldmeadow, C., Deelen, J., Perola, M., Zhao, J. H., Feenstra, B., Alizadeh, B. Z., Boezen, H. M., Franke, L., van der Harst, P., Navis, G., Rots, M., Snieder, H., Swertz, M., Wolffenbuttel, B. H. R., Wijmenga, C., Amini, M., Benjamin, E., Chasman, D. I., Dehghan, A., Ahluwalia, T. S., Meigs, J., Tracy, R., Bis, J., Eiriksdottir, G., Pankratz, N., Gross, M., Rainer, A., Wilson, J. G., Psaty, B. M., Dupuis, J., Prins, B., Vaso, U., Stathopoulou, M., Lehtimaki, T., Koenig, W., Jamshidi, Y., Siest, S., Uitterlinden, A. G., Abdollahi, M., Schnabel, R., Schick, U. M., Nolte, I. M., Kraja, A., Hsu, Y. -H., Tylee, D. S., Zwicker, A., Uher, R., Davey-Smith, G., Morrison, A. C., Hicks, A., van Duijn, C. M., Ward-Caviness, C., Boerwinkle, E., Rotter, J., Rice, K., Lange, L., de Geus, E., Morris, A. P., Makela, K. M., Stacey, D., Eriksson, J., Frayling, T. M., Slagboom, E. P., Lahti, J., Schraut, K. E., Fornage, M., Suktitipat, B., Chen, W. -M., Li, X., Nutile, T., Malerba, G., Luan, J., Bak, T., Schork, N., Del Greco, M. F., Thiering, E., Mahajan, A., Marioni, R. E., Mihailov, E., Ozel, A. B., Zhang, W., Nethander, M., Cheng, Y. -C., Aslibekyan, S., Ang, W., Gandin, I., Yengo, L., Portas, L., Kooperberg, C., Hofer, E., Rajan, K. B., Schurmann, C., den Hollander, W., Zhao, J., Draisma, H. H. M., Ford, I., Timpson, N., Teumer, A., Huang, H., Wahl, S., Liu, Y., Huang, J., Uh, H. -W., Geller, F., Joshi, P. K., Yanek, L. R., Trabetti, E., Lehne, B., Vozzi, D., Verbanck, M., Biino, G., Saba, Y., Meulenbelt, I., O'Connell, J. R., Laakso, M., Giulianini, F., Magnusson, P. K. E., Ballantyne, C. M., Hottenga, J. J., Montgomery, G. W., Rivadineira, F., Rueedi, R., Steri, M., Herzig, K. -H., Stott, D. J., Menni, C., Franberg, M., S, t. Pourcain B., Felix, S. B., Pers, T. H., Bakker, S. J. L., Kraft, P., Peters, A., Vaidya, D., Delgado, G., Smit, J. H., Grossmann, V., Sinisalo, J., Seppala, I., Williams, S. R., Holliday, E. G., Moed, M., Langenberg, C., Raikkonen, K., Ding, J., Campbell, H., Sale, M. M., Chen, Y. -D. I., James, A. L., Ruggiero, D., Soranzo, N., Hartman, C. A., Smith, E. N., Berenson, G. S., Fuchsberger, C., Hernandez, D., Tiesler, C. M. T., Giedraitis, V., Liewald, D., Fischer, K., Mellstrom, D., Larsson, A., Wang, Y., Scott, W. R., Lorentzon, M., Beilby, J., Ryan, K. A., Pennell, C. E., Vuckovic, D., Balkau, B., Concas, M. P., Schmidt, R., Mendes de Leon, C. F., Bottinger, E. P., Kloppenburg, M., Paternoster, L., Boehnke, M., Musk, A. W., Willemsen, G., Evans, D. M., Madden, P. A. F., Kahonen, M., Kutalik, Z., Zoledziewska, M., Karhunen, V., Kritchevsky, S. B., Sattar, N., Lachance, G., Clarke, R., Harris, T. B., Raitakari, O. T., Attia, J. R., van Heemst, D., Kajantie, E., Sorice, R., Gambaro, G., Scott, R. A., Hicks, A. A., Ferrucci, L., Standl, M., Lindgren, C. M., Starr, J. M., Karlsson, M., Lind, L., Li, J. Z., Chambers, J. C., Mori, T. A., de Geus, E. J. C. N., Heath, A. C., Martin, N. G., Auvinen, J., Buckley, B. M., de Craen, A. J. M., Waldenberger, M., Strauch, K., Meitinger, T., Scott, R. J., Mcevoy, M., Beekman, M., Bombieri, C., Ridker, P. M., Mohlke, K. L., Pedersen, N. L., Boomsma, D. I., Whitfield, J. B., Strachan, D. P., Hofman, A., Vollenweider, P., Cucca, F., Jarvelin, M. -R., Jukema, J. W., Spector, T. D., Hamsten, A., Zeller, T., Nauck, M., Gudnason, V., Qi, L., Grallert, H., Borecki, I. B., Rotter, J. I., Marz, W., Wild, P. S., Lokki, M. -L., Boyle, M., Salomaa, V., Melbye, M., Eriksson, J. G., Wilson, J. F., Penninx, B. W. J. H., Becker, D. M., Worrall, B. B., Gibson, G., Krauss, R. M., Ciullo, M., Zaza, G., Wareham, N. J., Oldehinkel, A. J., Palmer, L. J., Murray, S. S., Pramstaller, P. P., Bandinelli, S., Heinrich, J., Ingelsson, E., Deary, I. J., Magi, R., Vandenput, L., Desch, K. C., Kooner, J. S., Ohlsson, C., Hayward, C., Shuldiner, A. R., Arnett, D. K., Beilin, L. J., Robino, A., Froguel, P., Pirastu, M., Jess, T., Loos, R. J. F., Evans, D. A., Schmidt, H., Slagboom, P. E., Tracy, R. P., Visvikis-Siest, S., Reiner, A. P., Bis, J. C., Franco, O. H., Benjamin, E. J., AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Graduate School, Epidemiology, Internal Medicine, Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), VU University medical center, Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Methodology, APH - Digital Health, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Universität Heidelberg [Heidelberg], University of Verona (UNIVR), Department of Molecular and Experimental Medicine, The Scripps Research Institute, The Scripps Research Institute, Université Grenoble Alpes - UFR Sciences de l'Homme et de la Société (UGA UFR SHS), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), IT University of Copenhagen, Technical University of Denmark [Lyngby] (DTU), Consiglio Nazionale delle Ricerche (CNR), University of Virginia [Charlottesville], Université de Lausanne (UNIL), University of Oxford [Oxford], University of Newcastle [Australia] (UoN), Centre d'économie industrielle i3 (CERNA i3), Centre National de la Recherche Scientifique (CNRS)-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Helmholtz-Zentrum München (HZM), Laboratoire Interuniversitaire des Systèmes Atmosphériques (LISA (UMR_7583)), Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Universitätsmedizin der Johannes-Gutenberg Universität Mainz, University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Cardiff University-Medical Research Council, University of California-University of California, and DE CARVALHO, Philippe

Subjects
0301 basic medicine, Male, Netherlands Twin Register (NTR), Bipolar Disorder, LD SCORE REGRESSION, [SDV]Life Sciences [q-bio], Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, Body Mass Index, inflammatory disorder, 80 and over, WIDE ASSOCIATION, EPIDEMIOLOGY, ta318, International HapMap Project, Child, Genetics (clinical), 2. Zero hunger, Genetics, Genetics & Heredity, Aged, 80 and over, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, C-reactive proteingenome-wide association studyinflammationMendelian randomizationinflammatory disordersDEPICTcoronary artery diseaseschizophreniasystem biology, system biology, DEPICT, Mendelian Randomization Analysis, 11 Medical And Health Sciences, Middle Aged, C-reactive protein, coronary artery disease, genome-wide association study, inflammation, inflammatory disorders, Mendelian randomization, schizophrenia, Adolescent, Adult, Aged, Biomarkers, C-Reactive Protein, Female, Genetic Loci, Genome-Wide Association Study, Humans, Inflammation, Liver, Metabolic Networks and Pathways, Schizophrenia, Young Adult, 3. Good health, [SDV] Life Sciences [q-bio], Medical genetics, Biomarker (medicine), Life Sciences & Biomedicine, Human, medicine.medical_specialty, CHARGE Inflammation Working Group, Biology, IMMUNITY, ta3111, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, CORONARY-HEART-DISEASE, Mendelian Randomization Analysi, 1000 Genomes Project, METAANALYSIS, Genetic association, [SDV.GEN]Life Sciences [q-bio]/Genetics, Science & Technology, ta1184, Metabolic Networks and Pathway, Biomarker, INSTRUMENTS, 06 Biological Sciences, 030104 developmental biology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, LifeLines Cohort Study
Abstract

International audience; C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.Copyright © 2018 American Society of Human Genetics. All rights reserved.

Published
2018

4. Novel 6p21.3 Risk Haplotype Predisposes to Acute Coronary Syndrome

Author

Johanna Nokelainen, Mikko I. Mäyränpää, Perttu Salo, Krista Salli, Aki S. Havulinna, Marja Marchesani, Juhani Junttila, Heikki J. Niemi, Heikki V. Huikuri, Pekka J. Karhunen, Jani Lappalainen, Markku S. Nieminen, Jaume Marrugat, Marja-Liisa Lokki, Annika Wennerström, Roberto Elosua, Riitta Paakkanen, Veikko Salomaa, Markus Perola, Satu Männistö, Petri T. Kovanen, Aarno Palotie, Efthymia Vlachopoulou, Kjell Nikus, T. Petteri Arstila, Juha Sinisalo, Carla Lluis-Ganella, and Markku Eskola

Subjects
Male, 0301 basic medicine, Acute coronary syndrome, Single-nucleotide polymorphism, Genome-wide association study, Human leukocyte antigen, Major histocompatibility complex, Polymorphism, Single Nucleotide, Cohort Studies, 03 medical and health sciences, Th2 Cells, 0302 clinical medicine, Risk Factors, Genotype, Genetics, medicine, Humans, Acute Coronary Syndrome, Allele, Genetics (clinical), Aged, Aged, 80 and over, Membrane Glycoproteins, Butyrophilins, biology, Macrophages, Haplotype, Middle Aged, medicine.disease, Coronary Vessels, Plaque, Atherosclerotic, 3. Good health, 030104 developmental biology, Haplotypes, Immunology, biology.protein, Female, Cardiology and Cardiovascular Medicine, HLA-DRB1 Chains, 030215 immunology
Abstract

Background— The HLA-DRB1*01 allele of the human leukocyte antigen has been associated with acute coronary syndrome. Genome-wide association studies have revealed associations with human leukocyte antigen and non–human leukocyte antigen genes of 3 major histocompatibility complex gene classes but not at allelic level. Methods and Results— We conducted a large-scale genetic analysis on a case–control cohort comprising 5376 acute coronary syndrome cases and 4852 unrelated controls from 4 populations of 2 European countries. We analyzed the risk candidate allele of HLA-DRB1*01 by genomic real-time polymerase chain reaction together with high-density single nucleotide polymorphisms of the major histocompatibility complex to precisely identify risk loci for acute coronary syndrome with effective clinical implications. We found a risk haplotype for the disease containing single nucleotide polymorphisms from BTNL2 and HLA-DRA genes and the HLA-DRB1*01 allele. The association of the haplotype appeared in 3 of the 4 populations, and the direction of the effect was consistent in the fourth. Coronary samples from subjects homozygous for the disease-associated haplotype showed higher BTNL2 mRNA levels ( r =0.760; P + FOXP3 + regulatory T cell proliferation significantly (blocking versus nonblocking; P Conclusions— In cases with the risk haplotype for acute coronary syndrome, these results suggest involvement of enhanced immune reactions. BTNL2 may have an inhibitory effect on FOXP3 + T cell proliferation, especially in patients homozygous for the risk alleles. Clinical Trial Registration— https://www.clinicaltrials.gov ; Unique Identifier: NCT00417534.

Published
2016

5. Multi-ethnic genome-wide association study for atrial fibrillation

Author

Marcus E. Kleber, Raji P. Grewal, Yingchang Lu, Sanghamitra Mohanty, Harry J.G.M. Crijns, Han Sun, Ilkka Seppälä, Jonathan D. Smith, Albert Hofman, Yii-Der Ida Chen, Diane Fatkin, Patrik K. E. Magnusson, Pil Sung Yang, Jari Laurikka, Saman Nazarian, Peter W. Macfarlane, Natalia S. Rost, Sekar Kathiresan, Heribert Schunkert, Sandosh Padmanabhan, Tõnu Esko, Bruno H. Stricker, Rebecca Gutmann, Alfredo José Mansur, Jonathan Rosand, Jesper Hastrup Svendsen, Alvaro Alonso, J. Gustav Smith, Benjamin Neumann, John Barnard, Christopher D. Anderson, Joanna Pera, Samir Saba, Lynne J. Hocking, Siew-Kee Low, Daniel I. Chasman, Patrick T. Ellinor, Nancy L. Pedersen, Stephan B. Felix, Vilmundur Gudnason, Kjell Nikus, Kahraman Tanriverdi, David J. Porteous, Samuel C. Dudley, Clive R. Pullinger, Tamara B. Harris, Barry London, Lorenz Risch, Ruth J. F. Loos, Rainer Malik, Isabelle C. Van Gelder, John F. Carlquist, Lena Refsgaard, Carolina Roselli, Albert Y. Sun, Man Li, Lenore J. Launer, Anders Hamsten, Svati H. Shah, Lin Y. Chen, Martina Müller-Nurasyid, Michiel Rienstra, Kent D. Taylor, Katharina Schramm, Jennifer A. Brody, Honghuang Lin, Eric Boerwinkle, Rozenn N. Lemaitre, Olle Melander, Hugh Calkins, Elsayed Z. Soliman, Moritz F. Sinner, Heather L. Bloom, Nicholas L. Smith, Nada Esa, John W. Cole, Maartje N. Niemeijer, David R. Van Wagoner, Anubha Mahajan, Roopinder K. Sandhu, Henry J. Lin, Jordi Jimenez-Conde, Ian Ford, Eue Keun Choi, Stacey Knight, Scott M. Damrauer, Markku Eskola, Claudia Schurman, Stuart A. Scott, Sara L. Pulit, Raymond Noordam, Mika Kähönen, Jay A. Montgomery, Agnieszka Slowik, Esra Gucuk Ipek, Joylene E. Siland, Lingyao Zeng, Andrew P. Morris, Oscar H. Franco, Bas L.J.H. Kietselaer, Adnan Kastrati, Dan E. Arking, José Eduardo Krieger, J. Wouter Jukema, Stefan Gustafsson, Nathan R. Tucker, Zachary T. Yoneda, Daniel Woo, Winfried März, Lauren Margolin, Uwe Völker, Stefan Kääb, Marju Orho-Melander, Lars Lind, Yoichiro Kamatani, Maris Teder-Laving, Paul M. Ridker, Bradford B. Worrall, Jaemin Shim, Bob Weijs, Ingrid E. Christophersen, Kenneth B. Margulies, James P. Cook, Graciela Delgado, Andrea Natale, Stefan Weiss, Gustav Ahlberg, Jie Huang, Guillaume Paré, M. Benjamin Shoemaker, Marcus Dörr, Arnljot Tveit, Elton A. M. P. Dudink, Thomas P. Cappola, Bruce M. Psaty, Alaa Shalaby, Gregory M. Marcus, Sébastien Thériault, Niek Verweij, Traci M. Bartz, Thorsten Kessler, Michael Morley, Xiuqing Guo, Alexandre C. Pereira, Efthymia Vlachopoulou, Albert V. Smith, Andrea R. V. R. Horimoto, David Conen, Erik Ingelsson, Jie Yao, Raul Weiss, David D. McManus, Michiaki Kubo, Lu-Chen Weng, Michael A. Rosenberg, Nona Sotoodehnia, Jennifer E. Huffman, Hui Nam Pak, Dan M. Roden, Peter Weeke, Joshua C. Bis, Archie Campbell, Marta Ribasés, Renee Johnson, Renate B. Schnabel, Christian M. Shaffer, Krishna G. Aragam, Seung Hoan Choi, André G. Uitterlinden, Morten S. Olesen, Toshihiro Tanaka, Daniel J. Rader, Mina K. Chung, Stella Trompet, Steven A. Lubitz, Martin Dichgans, Peter Almgren, Christine M. Albert, Blair H. Smith, Petra Katschnig-Winter, Joshua C. Denny, Christopher Newton-Cheh, Paulus Kirchhof, Namrata Gupta, Emelia J. Benjamin, Stefanie Aeschbacher, Marja-Liisa Lokki, Jorge A. Wong, Quinn S. Wells, Jussi Hernesniemi, Cecilia M. Lindgren, Mark Chaffin, Kaoru Ito, Jerome I. Rotter, Michael J. Cutler, Kerri L. Wiggins, Maryam Kavousi, Nathan A. Bihlmeyer, Bastiaan Geelhoed, Susan R. Heckbert, Caroline Hayward, Alexander Teumer, Paul L. Huang, Terho Lehtimäki, Juha Sinisalo, John P. Kane, Kirsten Leineweber, Tanja Zeller, Hong Euy Lim, Kathryn L. Lunetta, Brian R. Daniels, Heidi Oellers, Biqi Wang, Pim van der Harst, Peter M. Nilsson, Dawood Darbar, Erwin B. Bottinger, Leo-Pekka Lyytikäinen, Epidemiology, Internal Medicine, RS: Carim - H01 Clinical atrial fibrillation, Cardiologie, MUMC+: MA Cardiologie (3), RS: CARIM - R2.01 - Clinical atrial fibrillation, RS: CARIM - R3.11 - Imaging, MUMC+: MA Med Staf Spec Cardiologie (9), MUMC+: MA Med Staf Artsass Cardiologie (9), Cardiovascular Centre (CVC), and MUMC+: MA Cardiologie (9)

Subjects
0301 basic medicine, medicine.medical_specialty, Identification, Annotation, Quantitative Trait Loci, Genome-wide association study, 030204 cardiovascular system & hematology, Quantitative trait locus, Biology, methods [Genome-Wide Association Study], Gene, genetics [Ethnic Groups], Article, DISEASE, 03 medical and health sciences, COMPONENTS-ANALYSIS, 0302 clinical medicine, ddc:570, Atrial Fibrillation, Cardiac conduction, Ethnicity, Genetics, medicine, Humans, Genetic Predisposition to Disease, genetics [Atrial Fibrillation], Genetic association, Imputation, ethnology [Atrial Fibrillation], Loci, Case-control study, Variants, METANÁLISE, Polymorphic ventricular-tachycardia, 030104 developmental biology, GWAS CATALOG, Susceptibility, Case-Control Studies, Expression quantitative trait loci, genetics [Ethnicity], Medical genetics, Transcriptome, Imputation (genetics), Mutations, Genome-Wide Association Study
Abstract

Atrial fibrillation (AF) affects more than 33 million individuals worldwide 1 and has a complex heritability 2 . We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

Published
2018

6. Genetic Variants Contributing to Circulating Matrix Metalloproteinase 8 Levels and Their Association With Cardiovascular Diseases

Author

Pirkko J. Pussinen, Wolfgang Sattler, Taina Tervahartiala, Juha Sinisalo, Markus Perola, Timo Sorsa, Seppo Meri, Aki S. Havulinna, Veikko Salomaa, Aino Salminen, Efthymia Vlachopoulou, Marja-Liisa Lokki, and Markku S. Nieminen

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Neutrophils, Population, Genome-wide association study, Single-nucleotide polymorphism, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Genetics, medicine, Humans, Genetic Predisposition to Disease, Allele, education, Complement Activation, Genetics (clinical), Aged, education.field_of_study, business.industry, Genetic Variation, Middle Aged, 3. Good health, Complement system, Minor allele frequency, Matrix Metalloproteinase 8, 030104 developmental biology, Endocrinology, Cardiovascular Diseases, Factor H, Alternative complement pathway, Female, Cardiology and Cardiovascular Medicine, business, Genome-Wide Association Study
Abstract

Background— Matrix metalloproteinase 8 (MMP-8) is a proinflammatory enzyme expressed mainly by neutrophils. Elevated serum and plasma concentrations of MMP-8 are associated with the risk for and outcome of cardiovascular diseases (CVDs). The origin of circulating MMP-8 is not completely clear. Methods and Results— We performed a genome-wide association study of serum MMP-8 levels in 2 populations comprising altogether 6049 individuals. Moreover, we studied whether MMP-8–associated variants are linked to increased risk of CVDs and overall mortality in >20 000 subjects. The strongest association with serum MMP-8 was found in locus 1q31.3, containing the gene for complement factor H (lead single nucleotide polymorphism: rs800292; P =2.4×10 –35 ). In functional experiments, activation of the alternative pathway of complement in the carriers of rs800292 minor allele (Ile62 in factor H) led to decreased release of MMP-8 from neutrophils compared with the major allele (Val62 in factor H). Another association was detected in 1q21.3, containing genes S100A8 , S100A9 , and S100A12 (strongest association: rs1560833; P =5.3×10 –15 ). The minor allele of rs1560833 was inversely associated with CVD (odds ratio [95% confidence interval]: 0.90 [0.82–0.99]; P =0.032) and the time to incident CVD event (hazard ratio [95% confidence interval]: 0.91 [0.84–0.99]; P =0.032) in men but not in women. Conclusions— According to our results, the activation of the alternative pathway of the complement system strongly contributes to serum MMP-8 concentration. Genetic polymorphism in S100A9–S100A12–S100A8 locus affects serum and plasma MMP-8 and shows a suggestive association with the risk of CVDs. Our results show that genetic variation determines a significant portion of circulating MMP-8 concentrations.

Published
2017

7. The Impact of Selection Bias on Estimation of Subsequent Event Risk

Author

Yi-Juan Hu, Amand F. Schmidt, Frank Dudbridge, Michael V. Holmes, James M. Brophy, Vinicius Tragante, Ziyi Li, Peizhou Liao, Arshed A. Quyyumi, Raymond O. McCubrey, Benjamin D. Horne, Aroon D. Hingorani, Folkert W. Asselbergs, Riyaz S. Patel, Qi Long, Axel Åkerblom, Ale Algra, Hooman Allayee, Peter Almgren, Jeffrey L. Anderson, Maria G. Andreassi, Chiara V. Anselmi, Diego Ardissino, Benoit J. Arsenault, Christie M. Ballantyne, Ekaterina V. Baranova, Hassan Behloui, Thomas O. Bergmeijer, Connie R. Bezzina, Eythor Bjornsson, Simon C. Body, Bram Boeckx, Eric (H.) Boersma, Eric Boerwinkle, Peter Bogaty, Peter S. Braund, Lutz P. Breitling, Hermann Brenner, Carlo Briguori, Jasper J. Brugts, Ralph Burkhardt, Vicky A. Cameron, John F. Carlquist, Clara Carpeggiani, Kathryn F. Carruthers, Gavino Casu, Gianluigi Condorelli, Sharon Cresci, Nicolas Danchin, Ulf de Faire, John Deanfield, Graciela Delgado, Panos Deloukas, Kenan Direk, Robert N. Doughty, Heinz Drexel, Nubia E. Duarte, Marie-Pierre Dubé, Line Dufresne, James C. Engert, Niclas Eriksson, Natalie Fitzpatrick, Luisa Foco, Ian Ford, Keith A.A. Fox, Bruna Gigante, Crystel M. Gijsberts, Domenico Girelli, Yan Gong, Daniel F. Gudbjartsson, Emil Hagström, Jaana Hartiala, Stanley L. Hazen, Claes Held, Anna Helgadottir, Harry Hemingway, Mahyar Heydarpour, Imo E. Hoefer, Kees Hovingh, Jaroslav A. Hubacek, Stefan James, Julie A. Johnson, J. Wouter Jukema, Marcin P. Kaczor, Karol A. Kaminski, Jiri Kettner, Marek Kiliszek, Marcus Kleber, Olaf H. Klungel, Daniel Kofink, Mika Kohonen, Salma Kotti, Pekka Kuukasjärvi, Bo Lagerqvist, Diether Lambrechts, Chim C. Lang, Jari O. Laurikka, Karin Leander, Vei-Vei Lee, Terho Lehtimäki, Andreas Leiherer, Petra A. Lenzini, Daniel Levin, Daniel Lindholm, Marja-Liisa Lokki, Paulo A. Lotufo, Leo-Pekka Lyytikäinen, B. Khan Mahmoodi, Anke H. Maitland-van der Zee, Nicola Martinelli, Winfried März, Nicola Marziliano, Ruth McPherson, Olle Melander, Ute Mons, Jochen D. Muehlschlegel, Joseph B. Muhlestein, Cristopher P. Nelson, Chris Newton Cheh, Oliviero Olivieri, Grzegorz Opolski, Colin N. Palmer, Guillaume Pare, Gerard Pasterkamp, Carl J. Pepine, Witold Pepinski, Alexandre C. Pereira, Anna P. Pilbrow, Louise Pilote, Jan Pitha, Rafal Ploski, A. Mark Richards, Christoph H. Saely, Nilesh J. Samani, Ayman Samman-Tahhan, Marek Sanak, Pratik B. Sandesara, Naveed Sattar, Markus Scholz, Agneta Siegbahn, Tabassome Simon, Juha Sinisalo, J. Gustav Smith, John A. Spertus, Kari Stefansson, Alexandre F.R. Stewart, David J. Stott, Wojciech Szczeklik, Anna Szpakowicz, Michael W.T. Tanck, Wilson H. Tang, Jean-Claude Tardif, Jur M. ten Berg, Andrej Teren, George Thanassoulis, Joachim Thiery, Gudmundur Thorgeirsson, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Adam Timmis, Stella Trompet, Frans van de Werf, Yolanda van der Graaf, Pim van der Haarst, Sander W. van der Laan, Ragnar O. Vilmundarson, Salim S. Virani, Frank L.J. Visseren, Efthymia Vlachopoulou, Lars Wallentin, Johannes Waltenberger, Els Wauters, Arthur A.M. Wilde, Erasmus MC other, Cardiology, Department of Marketing Management, Pathology, Clinical Genetics, PharmacoTherapy, -Epidemiology and -Economics, and ACS - Heart failure & arrhythmias

Subjects
COLLIDER BIAS, genetic association studies, media_common.quotation_subject, Coronary Disease, Disease, Genetic Diseases, Inborn/genetics, HEART-DISEASE, 030204 cardiovascular system & hematology, OBESITY PARADOX, Article, EXPLANATION, 03 medical and health sciences, 0302 clinical medicine, Genetic, Bias, Models, Statistics, Genetics, Medicine, Humans, selection bias, Genetics(clinical), False Positive Reactions, 030212 general & internal medicine, Genetics (clinical), Selection (genetic algorithm), confidence intervals, Selection Bias, Event (probability theory), Genetic association, media_common, risk, Selection bias, Observer Variation, Models, Genetic, business.industry, Hazard ratio, Genetic Diseases, Inborn, ASSOCIATION, Confidence interval, sample size, Inborn/genetics, Sample size determination, CARDIOVASCULAR-DISEASE, Genetic Diseases, alleles, INDEX-EVENT, business, Cardiology and Cardiovascular Medicine
Abstract

Background— Studies of recurrent or subsequent disease events may be susceptible to bias caused by selection of subjects who both experience and survive the primary indexing event. Currently, the magnitude of any selection bias, particularly for subsequent time-to-event analysis in genetic association studies, is unknown. Methods and Results— We used empirically inspired simulation studies to explore the impact of selection bias on the marginal hazard ratio for risk of subsequent events among those with established coronary heart disease. The extent of selection bias was determined by the magnitudes of genetic and nongenetic effects on the indexing (first) coronary heart disease event. Unless the genetic hazard ratio was unrealistically large (>1.6 per allele) and assuming the sum of all nongenetic hazard ratios was Conclusions— In most empirical settings, selection bias is expected to have a limited impact on genetic effect estimates of subsequent event risk. Nevertheless, because of undercoverage increasing with sample size, most confidence intervals will be over precise (not wide enough). When there is no effect modification by history of coronary heart disease, the false-positive rates of association tests will be close to nominal.

Published
2017

8. Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation

Author

Joshua C. Bis, Daniel I. Chasman, Archie Campbell, J. Wouter Jukema, Yoichiro Kamatani, Joylene E. Siland, Siegfried Perz, Jie Huang, Jorge A. Wong, Jared W. Magnani, Stefan Weiss, Caroline Hayward, Christopher D. Anderson, Carolina Roselli, Alexander P. Reiner, Maartje N. Niemeijer, Efthymia Vlachopoulou, David R. Van Wagoner, Elsayed Z. Soliman, Lenore J. Launer, Claudia Schurmann, Jeffrey Haessler, Joshua C. Denny, Qiong Yang, Mika Kähönen, Henry J. Lin, Lu-Chen Weng, Molong Li, Paul L. Huang, Terho Lehtimäki, Bruno H. Stricker, Lewin Eisele, Christopher Newton-Cheh, Marcus E. Kleber, Alexander Teumer, Rainer Malik, Juha Sinisalo, Siew-Kee Low, Xiaoyan Yin, Stéphanie Debette, Jennifer A. Brody, Marco V Perez, Derek Klarin, Farid Radmanesh, Ian Ford, Dan M. Roden, Paul M. Ridker, Jan Heeringa, Jonathan Rosand, Andrew P. Morris, Winfried März, Stefan Gustafsson, Xiuqing Guo, Nathan R. Tucker, Dawood Darbar, Daniel J. Rader, Martin Dichgans, Stefan Kääb, Lars Lind, Patrick T. Ellinor, Nancy L. Pedersen, Stefanie Aeschbacher, Erwin B. Bottinger, Leo-Pekka Lyytikäinen, Peter Lichtner, Marcus Dörr, Svati H. Shah, Lin Y. Chen, Alvaro Alonso, Marja-Liisa Lokki, Albert V. Smith, Guillaume Paré, Ruth J. F. Loos, Christine M. Albert, Markku Eskola, Jonathan D. Smith, Kjell Nikus, Martina Müller-Nurasyid, Yanick Hagemeijer, Lorenz Risch, Nona Sotoodehnia, Jussi Hernesniemi, Albert Y. Sun, Man Li, Jemma C. Hopewell, Olle Melander, Albert Hofman, Annette Peters, Pim van der Harst, Michiel Rienstra, Ilkka Seppälä, Kent D. Taylor, Charles Kooperberg, Moritz F. Sinner, Jerome I. Rotter, Stuart A. Scott, Toshihiro Tanaka, Steven A. Lubitz, Uwe Völker, Marju Orho-Melander, Patrik K. E. Magnusson, Jari Laurikka, M. Benjamin Shoemaker, Niek Verweij, J. Gustav Smith, José Eduardo Krieger, Sébastien Thériault, Andrea R. V. R. Horimoto, Natalia S. Rost, André G. Uitterlinden, Oscar H. Franco, David Conen, Cecilia M. Lindgren, Sekar Kathiresan, Michiaki Kubo, Marina Arendt, Graciela Delgado, Anders Hamsten, Rajat Deo, Lars Lannfelt, Sebastian Clauss, Sandosh Padmanabhan, Emelia J. Benjamin, Roopinder K. Sandhu, Bruce M. Psaty, Peter Weeke, Mark Chaffin, Traci M. Bartz, Erik Ingelsson, Alfredo José Mansur, Nathan A. Bihlmeyer, Christian M. Shaffer, Lynne J. Hocking, Stella Trompet, Melanie Waldenberger, Honghuang Lin, Stephan B. Felix, David J. Porteous, Vilmundur Gudnason, Eric Boerwinkle, Dan E. Arking, Alexandre C. Pereira, Bastiaan Geelhoed, Susan R. Heckbert, Jie Yao, Bradford B. Worrall, Ingrid E. Christophersen, Jennifer Kriebel, Peter Almgren, Blair H. Smith, Jennifer E. Huffman, Seung Hoan Choi, Mina K. Chung, Karl-Heinz Jöckel, Yingchang Lu, Yii-Der Ida Chen, Peter W. Macfarlane, John Barnard, Tamara B. Harris, Kathryn L. Lunetta, Stefanie Heilmann-Heimbach, Ganesh Chauhan, Epidemiology, Internal Medicine, and Cardiovascular Centre (CVC)

Subjects
0301 basic medicine, Quantitative Trait Loci, Medizin, genetics [White People], SNP, Genome-wide association study, 030204 cardiovascular system & hematology, Biology, SUSCEPTIBILITY, Bioinformatics, GENOMAS, ANNOTATION, White People, 03 medical and health sciences, 0302 clinical medicine, ddc:570, Genetic variation, Atrial Fibrillation, Genetics, medicine, Journal Article, TOOL, Humans, Genetic Predisposition to Disease, genetics [Atrial Fibrillation], GENOME-WIDE ASSOCIATION, Stroke, METAANALYSIS, Genetic association, RISK, genetics [Black or African American], GENETIC-VARIATION, Atrial fibrillation, medicine.disease, R1, 3. Good health, Black or African American, genetics [European Continental Ancestry Group], 030104 developmental biology, Genetic Loci, Heart failure, Meta-analysis, VISUALIZATION, genetics [African Americans], BURDEN, Genome-Wide Association Study
Abstract

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death(1,2). Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups(3-7). To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery(8).

Published
2017

9. Bringing Cardiovascular Research Onlife

Author

Efthymia Vlachopoulou

Subjects
0301 basic medicine, Publishing, Medical education, Biomedical Research, Physiology, business.industry, Information Dissemination, Cardiovascular research, MEDLINE, Cardiology, 030204 cardiovascular system & hematology, Access to Information, 03 medical and health sciences, Access to information, 030104 developmental biology, 0302 clinical medicine, Physiology (medical), Political science, Humans, Diffusion of Innovation, Periodicals as Topic, Cardiology and Cardiovascular Medicine, business
Published
2017

10. Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study

Author

Robert N. Doughty, Marcus E. Kleber, Ulrich Laufs, Aroon D. Hingorani, Vinicius Tragante, Joachim Thiery, Eva Ringdal Pedersen, Sarah Triem, Andreas Leiherer, Alexandra Filips, Kenan Direk, Alexandre F.R. Stewart, Petra A. Lenzini, W.H. Wilson Tang, Thimoteus Speer, Roelof A.J. Smit, Hooman Allayee, Eric Boerwinkle, Ioannis Petrakis, George Thanassoulis, Christoph Sinning, Domenico Girelli, Heinrich V. Groesdonk, Yan Gong, Lutz P. Breitling, A. Mark Richards, Vicky A. Cameron, Benjamin D. Horne, Ruth McPherson, Gard Frodahl Tveitevåg Svingen, Dietrich Rothenbacher, Christopher Labos, Jaana Hartiala, Louise Pilote, Imo E. Hoefer, Christie M. Ballantyne, Ute Mons, Wolfgang Koenig, Bernhard K. Krämer, Stephen Zewinger, Vei-Vei Lee, Danilo Fliser, Ragnar O. Vilmundarson, Stefan Blankenberg, Julie A. Johnson, Riyaz S. Patel, Mira Klug, Christian Werner, Efthymia Vlachopoulou, H Brenner, Daniel Kofink, Michael V. Holmes, James C. Engert, Christopher P. Nelson, Agneta Siegbahn, Axel Mündlein, J. Wouter Jukema, Marek Sanak, Marcin P. Kaczor, Peter S. Braund, Markus Scholz, Niclas Eriksson, Markku S. Nieminen, Christoph Waldeyer, Salim S. Virani, Winfried März, Raymond O McCubrey, Stanley L. Hazen, Heinz Drexel, Yi-An Ko, Nicola Martinelli, Renate B. Schnabel, Hubert Scharnagl, Oliviero Olivieri, Wojciech Szczeklik, Grethe S. Tell, Nilesh J. Samani, Gustav Smith, James M. Brophy, Ottar Nygård, Naveed Sattar, Juha Sinisalo, Richard T. Jennings, Tatjana Stojakovic, Stella Trompet, Emil Hagström, Axel Åkerblom, John A. Spertus, Claes Held, Gerard Pasterkamp, Frank Beutner, Folkert W. Asselbergs, Anna P. Pilbrow, Rhonda M. Cooper-DeHoff, Arshed A. Quyyumi, Christoph H. Saely, Lars Wallentin, Sharon Cresci, Igor Karp, Amand F. Schmidt, Peter Bogaty, Reijo Laaksonen, Graciela E. Delgado, Karl J. Lackner, Transplantation Laboratory, Medicum, University of Helsinki, Department of Medicine, Clinicum, University Management, and Doctoral Programme in Clinical Research

Subjects
Male, Endocrinology, Diabetes and Metabolism, Coronary Disease, Disease, 030204 cardiovascular system & hematology, Cardiovascular System, Cohort Studies, 0302 clinical medicine, Endocrinology, Risk Factors, Risk of mortality, Medicine, 030212 general & internal medicine, Myocardial infarction, lipoprotein(a) concentrations, LPA genetic variants, mortality, coronary heart disease, education.field_of_study, Framingham Risk Score, biology, Lipoprotein(a), Middle Aged, Prognosis, 3. Good health, Europe, Survival Rate, Diabetes and Metabolism, Cardiovascular Diseases, Female, Cohort study, medicine.medical_specialty, Population, education, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Internal medicine, Internal Medicine, Journal Article, Humans, Genetic Association Studies, business.industry, medicine.disease, Blood pressure, 3121 General medicine, internal medicine and other clinical medicine, biology.protein, 3111 Biomedicine, business, Biomarkers
Abstract

Background: \ud \ud Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear.\ud \ud Methods: \ud \ud We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts.\ud \ud Findings: \ud \ud The median follow-up was 9·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1·44, 95% CI 1·14–1·83) and the presence of either LPA SNP (1·88, 1·40–2·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0·95, 0·81–1·11 and either LPA SNP 1·10, 0·92–1·31) or cardiovascular mortality (0·99, 0·81–1·2 and 1·13, 0·90–1·40, respectively) or in the validation studies.\ud \ud Interpretation: \ud \ud In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established.\ud \ud Funding: \ud \ud Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung für Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny.

Published
2017

11. Genetic Variation on the BAT1-NFKBIL1-LTA Region of Major Histocompatibility Complex Class III Associates with Periodontitis

Author

Markku S. Nieminen, Matti Knuuttila, Sisko Huumonen, Kåre Buhlin, Juha Sinisalo, Pirkko J. Pussinen, Anna Liisa Suominen, Efthymia Vlachopoulou, Johanna Contreras, K. A. Elisa Kallio, Marja Marchesani, Päivi Mäntylä, Susanna Paju, Markus Perola, Marcela Hernández, and Marja-Liisa Lokki

Subjects
Lymphotoxin alpha, Immunology, Population, Single-nucleotide polymorphism, Genome-wide association study, Biology, History, 18th Century, Polymorphism, Single Nucleotide, Microbiology, Severe periodontitis, History, 17th Century, Major Histocompatibility Complex, medicine, Humans, Aggressive periodontitis, Genetic Predisposition to Disease, Periodontitis, education, Host Response and Inflammation, education.field_of_study, Genome, Human, Haplotype, Genetic Variation, medicine.disease, Health Surveys, Protein Structure, Tertiary, 3. Good health, Infectious Diseases, Haplotypes, Parasitology
Abstract

Periodontitis is a chronic inflammatory disease with a multifactorial etiology. We investigated whether human major histocompatibility complex (MHC) polymorphisms (6p21.3) are associated with periodontal parameters. Parogene 1 population samples ( n = 169) were analyzed with 13,245 single nucleotide polymorphisms (SNPs) of the MHC region. Eighteen selected SNPs ( P ≤ 0.001) were replicated in Parogene 2 population samples ( n = 339) and the Health 2000 Survey ( n = 1,420). All subjects had a detailed clinical and radiographic oral health examination. Serum lymphotoxin-α (LTA) concentrations were measured in the Parogene populations, and the protein was detected in inflamed periodontal tissue. In the Parogene 1 population, 10 SNPs were associated with periodontal parameters. The strongest associations emerged from the parameters bleeding on probing (BOP) and a probing pocket depth (PPD) of ≥6 mm with the genes BAT1 , NFKBIL1 , and LTA . Six SNPs, rs11796, rs3130059, rs2239527, rs2071591, rs909253, and rs1041981 ( r 2 , ≥0.92), constituted a risk haplotype. In the Parogene 1 population, the haplotype had the strongest association with the parameter BOP, a PPD of ≥6 mm, and severe periodontitis with odds ratios (95% confidence intervals) of 2.63 (2.21 to 3.20), 2.90 (2.37 to 3.52), and 3.10 (1.63 to 5.98), respectively. These results were replicated in the other two populations. High serum LTA concentrations in the Parogene population were associated with the periodontitis risk alleles of the LTA SNPs (rs909253 and rs1041981) of the haplotype. In addition, the protein was expressed in inflamed gingival connective tissue. We identified a novel BAT1-NFKBIL1-LTA haplotype as a significant contributor to the risk of periodontitis. The genetic polymorphisms in the MHC class III region may be functionally important in periodontitis susceptibility.

Published
2014

12. Plasma ceramides predict cardiovascular death in patients with stable coronary artery disease and acute coronary syndromes beyond LDL-cholesterol

Author

Hubert Scharnagl, Stephan Windecker, Grethe S. Tell, Juha Sinisalo, Marja-Liisa Lokki, Lorenz Räber, Reijo Laaksonen, Markku S. Nieminen, Dimple Kauhanen, François Mach, Nicolas Rodondi, Reini Hurme, Thomas F. Lüscher, Ottar Nygård, Christian M. Matter, Winfried März, Thorsten Hornemann, Tatjana Stojakovic, Roland Klingenberg, Marko Sysi-Aho, Baris Gencer, Efthymia Vlachopoulou, Mika Hilvo, Matti Suoniemi, Terhi Vihervaara, Kim Ekroos, Peter Jüni, Eva Ringdal Pedersen, University of Zurich, Laaksonen, Reijo, Transplantation Laboratory, Medicum, Clinicum, Department of Medicine, and Kardiologian yksikkö

Subjects
0301 basic medicine, medicine.medical_specialty, education, 610 Medicine & health, Coronary Artery Disease, 030204 cardiovascular system & hematology, Ceramides, Coronary artery disease, 2705 Cardiology and Cardiovascular Medicine, Cardiovascular death, Ceramide, 03 medical and health sciences, 0302 clinical medicine, 360 Social problems & social services, Risk Factors, Internal medicine, 540 Chemistry, medicine, Humans, LDL-cholesterol, In patient, Prospective Studies, 10038 Institute of Clinical Chemistry, Ldl cholesterol, business.industry, Fasttrack Clinical Research, Coronary arteriosclerosis, Acute Coronary Syndrome, Biomarkers, Cholesterol, LDL, Prognosis, Acute coronary syndrome, Biomarker, Risk prediction, medicine.disease, 3. Good health, Surgery, Editor's Choice, 030104 developmental biology, 3121 General medicine, internal medicine and other clinical medicine, Cardiology, 10209 Clinic for Cardiology, LDL Cholesterol Lipoproteins, Fast Track, lipids (amino acids, peptides, and proteins), 3111 Biomedicine, Cardiology and Cardiovascular Medicine, business
Abstract

Aims The aim was to study the prognostic value of plasma ceramides (Cer) as cardiovascular death (CV death) markers in three independent coronary artery disease (CAD) cohorts. Methods and results Corogene study is a prospective Finnish cohort including stable CAD patients (n = 160). Multiple lipid biomarkers and C-reactive protein were measured in addition to plasma Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0), and Cer(d18:1/24:1). Subsequently, the association between high-risk ceramides and CV mortality was investigated in the prospective Special Program University Medicine - Inflammation in Acute Coronary Syndromes (SPUM-ACS) cohort (n = 1637), conducted in four Swiss university hospitals. Finally, the results were validated in Bergen Coronary Angiography Cohort (BECAC), a prospective Norwegian cohort study of stable CAD patients. Ceramides, especially when used in ratios, were significantly associated with CV death in all studies, independent of other lipid markers and C-reactive protein. Adjusted odds ratios per standard deviation for the Cer(d18:1/16:0)/Cer(d18:1/24:0) ratio were 4.49 (95% CI, 2.24-8.98), 1.64 (1.29-2.08), and 1.77 (1.41-2.23) in the Corogene, SPUM-ACS, and BECAC studies, respectively. The Cer(d18:1/16:0)/Cer(d18:1/24:0) ratio improved the predictive value of the GRACE score (net reclassification improvement, NRI = 0.17 and ΔAUC = 0.09) in ACS and the predictive value of the Marschner score in stable CAD (NRI = 0.15 and ΔAUC = 0.02). Conclusions Distinct plasma ceramide ratios are significant predictors of CV death both in patients with stable CAD and ACS, over and above currently used lipid markers. This may improve the identification of high-risk patients in need of more aggressive therapeutic interventions.

Published
2016

13. Associations of functional alanine-glyoxylate aminotransferase 2 gene variants with atrial fibrillation and ischemic stroke

Author

Kari-Matti Mäkelä, Mika Kähönen, Steve Bevan, Jussi Hernesniemi, Hugh S. Markus, Tuomas Koskinen, Efthymia Vlachopoulou, Martin Dichgans, Nina Mononen, Catherine Sudlow, Leo-Pekka Lyytikäinen, Winfried März, Ilkka Seppälä, Peter M. Rothwell, Graciela Delgado, Reijo Laaksonen, Marcus E. Kleber, Juha Sinisalo, Hubert Scharnagl, Terho Lehtimäki, Niku Oksala, Transplantation Laboratory, Medicum, Clinicum, University of Helsinki, Department of Medicine, and Kardiologian yksikkö

Subjects
Male, 0301 basic medicine, Pathology, Heart disease, BLOOD-PRESSURE, Genome-wide association study, 030204 cardiovascular system & hematology, Cohort Studies, 0302 clinical medicine, Atrial Fibrillation, Odds Ratio, OXIDATIVE STRESS, Stroke, POPULATION, ASYMMETRIC DIMETHYLARGININE, education.field_of_study, Multidisciplinary, Angiography, Atrial fibrillation, Middle Aged, Coronary Vessels, 3. Good health, Cohort, Cardiology, Female, medicine.medical_specialty, Genotype, Population, Mutation, Missense, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Internal medicine, medicine, Humans, SYMMETRIC DIMETHYLARGININE, GENOME-WIDE ASSOCIATION, education, METAANALYSIS, Alleles, Transaminases, Aged, NITRIC-OXIDE, business.industry, MORTALITY, Case-control study, Odds ratio, ta3121, medicine.disease, ADMA, Logistic Models, 030104 developmental biology, 3121 General medicine, internal medicine and other clinical medicine, Case-Control Studies, Chronic Disease, C400 Genetics, business
Abstract

Asymmetric and symmetric dimethylarginines (ADMA and SDMA) impair nitric oxide bioavailability and have been implicated in the pathogenesis of atrial fibrillation (AF). Alanine–glyoxylate aminotransferase 2 (AGXT2) is the only enzyme capable of metabolizing both of the dimethylarginines. We hypothesized that two functional AGXT2 missense variants (rs37369, V140I; rs16899974, V498L) are associated with AF and its cardioembolic complications. Association analyses were conducted using 1,834 individulas with AF and 7,159 unaffected individuals from two coronary angiography cohorts and a cohort comprising patients undergoing clinical exercise testing. In coronary angiography patients without structural heart disease, the minor A allele of rs16899974 was associated with any AF (OR = 2.07, 95% CI 1.59-2.68) and with paroxysmal AF (OR = 1.98, 95% CI 1.44–2.74) and chronic AF (OR = 2.03, 95% CI 1.35–3.06) separately. We could not replicate the association with AF in the other two cohorts. However, the A allele of rs16899974 was nominally associated with ischemic stroke risk in the meta-analysis of WTCCC2 ischemic stroke cohorts (3,548 cases, 5,972 controls) and with earlier onset of first-ever ischemic stroke (360 cases) in the cohort of clinical exercise test patients. In conclusion, AGXT2 variations may be involved in the pathogenesis of AF and its age-related thromboembolic complications.

Published
2016

14. Chromosome X-Wide Association Study Identifies Loci for Fasting Insulin and Height and Evidence for Incomplete Dosage Compensation

Author

Johannes Kettunen, Samuli Ripatti, Claes Ladenvall, Marjo-Riitta Järvelin, Marja-Liisa Lokki, Antti-Pekka Sarin, Juha Sinisalo, Veikko Salomaa, Efthymia Vlachopoulou, Leif Groop, Johan G. Eriksson, Olli T. Raitakari, Terho Lehtimäki, Antti Jula, Taru Tukiainen, Markus Perola, Matti Pirinen, Institute for Molecular Medicine Finland, Haartman Institute (-2014), Transplantation Laboratory, Department of Medicine, Kardiologian yksikkö, Clinicum, Department of General Practice and Primary Health Care, Hjelt Institute (-2014), Biostatistics Helsinki, Quantitative Genetics, Complex Disease Genetics, Lääketieteen yksikkö - School of Medicine, and University of Tampere

Subjects
Male, Cancer Research, Genome-wide association study, VARIANTS, 0302 clinical medicine, Missing heritability problem, X Chromosome Inactivation, Insulin, Cation Transport Proteins, Genetics (clinical), X chromosome, Genetics & Heredity, Genetics, 0303 health sciences, Sex Characteristics, Dosage compensation, CARDIOVASCULAR RISK, Nuclear Proteins, Fasting, GENOME, VARIABILITY, Phenotype, Epigenetics, Female, SEX, Life Sciences & Biomedicine, Research Article, Adult, EXPRESSION, X-linked Nuclear Protein, GENES, lcsh:QH426-470, Biolääketieteet - Biomedicine, European Continental Ancestry Group, education, Locus (genetics), Single-nucleotide polymorphism, Endocrinology and Diabetes, Biology, GENOTYPE IMPUTATION, Polymorphism, Single Nucleotide, X-inactivation, White People, 03 medical and health sciences, Dosage Compensation, Genetic, Genome-Wide Association Studies, Humans, Molecular Biology, Ecology, Evolution, Behavior and Systematics, METAANALYSIS, 030304 developmental biology, Genetic association, 0604 Genetics, Chromosomes, Human, X, Science & Technology, DNA Helicases, Membrane Proteins, ta3121, Body Height, Fibroblast Growth Factors, lcsh:Genetics, COHORT PROFILE, 3111 Biomedicine, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract

The X chromosome (chrX) represents one potential source for the “missing heritability” for complex phenotypes, which thus far has remained underanalyzed in genome-wide association studies (GWAS). Here we demonstrate the benefits of including chrX in GWAS by assessing the contribution of 404,862 chrX SNPs to levels of twelve commonly studied cardiometabolic and anthropometric traits in 19,697 Finnish and Swedish individuals with replication data on 5,032 additional Finns. By using a linear mixed model, we estimate that on average 2.6% of the additive genetic variance in these twelve traits is attributable to chrX, this being in proportion to the number of SNPs in the chromosome. In a chrX-wide association analysis, we identify three novel loci: two for height (rs182838724 near FGF16/ATRX/MAGT1, joint P-value = 2.71×10−9, and rs1751138 near ITM2A, P-value = 3.03×10−10) and one for fasting insulin (rs139163435 in Xq23, P-value = 5.18×10−9). Further, we find that effect sizes for variants near ITM2A, a gene implicated in cartilage development, show evidence for a lack of dosage compensation. This observation is further supported by a sex-difference in ITM2A expression in whole blood (P-value = 0.00251), and is also in agreement with a previous report showing ITM2A escapes from X chromosome inactivation (XCI) in the majority of women. Hence, our results show one of the first links between phenotypic variation in a population sample and an XCI-escaping locus and pinpoint ITM2A as a potential contributor to the sexual dimorphism in height. In conclusion, our study provides a clear motivation for including chrX in large-scale genetic studies of complex diseases and traits., Author Summary The X chromosome (chrX) analyses have often been neglected in large-scale genome-wide association studies. Given that chrX contains a considerable proportion of DNA, we wanted to examine how the variation in the chromosome contributes to commonly studied phenotypes. To this end, we studied the associations of over 400,000 chrX variants with twelve complex phenotypes, such as height, in almost 25,000 Northern European individuals. Demonstrating the value of assessing chrX associations, we found that as a whole the variation in the chromosome influences the levels of many of these phenotypes and further identified three new genomic regions where the variants associate with height or fasting insulin levels. In one of these three associated regions, the region near ITM2A, we observed that there is a sex difference in the genetic effects on height in a manner consistent with a lack of dosage compensation in this locus. Further supporting this observation, ITM2A has been shown to be among those chrX genes where the X chromosome inactivation is incomplete. Identifying phenotype associations in regions like this where chrX allele dosages are not balanced between men and women can be particularly valuable in helping us to understand why some characteristics differ between sexes.

Published
2014

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