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Coronary Artery Disease: HELP
Articles by Themistocles L. Assimes
Based on 33 articles published since 2009
(Why 33 articles?)
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Between 2009 and 2019, Themistocles Assimes wrote the following 33 articles about Coronary Artery Disease.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Editorial Genetic Risk Scores in Premature Coronary Artery Disease: Still Only One Piece of the Prevention Puzzle. 2018

Assimes, Themistocles L / Herrington, David M. ·>From the Department of Medicine, Stanford University School of Medicine, Palo Alto, CA (T.L.A.) · and Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC (D.M.H.). ·Circ Genom Precis Med · Pubmed #29874182.

ABSTRACT: -- No abstract --

2 Review Leveraging information from genetic risk scores of coronary atherosclerosis. 2017

Assimes, Themistocles L / Salfati, Elias L / Del Gobbo, Liana C. ·aDepartment of Medicine bStanford Cardiovascular Institute, Stanford University, Stanford, California, USA. ·Curr Opin Lipidol · Pubmed #28207434.

ABSTRACT: PURPOSE OF REVIEW: Genome-wide association studies (GWAS) have identified ∼60 loci for coronary artery disease (CAD). Through genetic risk scores (GRSs), investigators are leveraging this genomic information to gain insights on both the fundamental mechanisms driving these associations as well as their utility in improving risk prediction. RECENT FINDINGS: GRSs of CAD track with the earliest atherosclerosis lesions in the coronary including fatty streaks and uncomplicated raised lesions. In multiple cohort studies, they predict incident CAD events independent of all traditional and lifestyle risk factors. The incorporation of SNPs with suggestive but not genome-wide association in GWAS into GRSs often increases the strength of these associations. GRS may also predict recurrent events and identify patients most likely to respond to statins. The effect of the GRS on discrimination metrics remains modest but the minimal degree of improvement needed for clinical utility is unknown. SUMMARY: Most novel loci for CAD identified through GWAS facilitate the formation of coronary atherosclerosis and stratify individuals based on their underlying burden of coronary atherosclerosis. GRSs may one day be routinely used in clinical practice to not only assess the risk of incident events but also to predict who will respond best to established prevention strategies.

3 Review Genetics: Implications for Prevention and Management of Coronary Artery Disease. 2016

Assimes, Themistocles L / Roberts, Robert. ·Department of Medicine, Stanford University School of Medicine, Stanford, California. Electronic address: tassimes@stanford.edu. · International Society for Cardiovascular Translational Research, University of Arizona College of Medicine, Phoenix, Arizona. ·J Am Coll Cardiol · Pubmed #28007143.

ABSTRACT: An exciting new era has dawned for the prevention and management of coronary artery disease (CAD) utilizing genetic risk variants. The recent identification of over 60 susceptibility loci for CAD confirms not only the importance of established risk factors, but also the existence of many novel causal pathways that are expected to improve our understanding of the genetic basis of CAD and facilitate the development of new therapeutic agents over time. Concurrently, Mendelian randomization studies have provided intriguing insights on the causal relationship between CAD-related traits, and highlight the potential benefits of long-term modifications of risk factors. Last, genetic risk scores of CAD may serve not only as prognostic, but also as predictive markers, and carry the potential to considerably improve the delivery of established prevention strategies. This review will summarize the evolution and discovery of genetic risk variants for CAD and their current and future clinical applications.

4 Review Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants. 2014

Dichgans, Martin / Malik, Rainer / König, Inke R / Rosand, Jonathan / Clarke, Robert / Gretarsdottir, Solveig / Thorleifsson, Gudmar / Mitchell, Braxton D / Assimes, Themistocles L / Levi, Christopher / O'Donnell, Christopher J / Fornage, Myriam / Thorsteinsdottir, Unnur / Psaty, Bruce M / Hengstenberg, Christian / Seshadri, Sudha / Erdmann, Jeanette / Bis, Joshua C / Peters, Annette / Boncoraglio, Giorgio B / März, Winfried / Meschia, James F / Kathiresan, Sekar / Ikram, M Arfan / McPherson, Ruth / Stefansson, Kari / Sudlow, Cathie / Reilly, Muredach P / Thompson, John R / Sharma, Pankaj / Hopewell, Jemma C / Chambers, John C / Watkins, Hugh / Rothwell, Peter M / Roberts, Robert / Markus, Hugh S / Samani, Nilesh J / Farrall, Martin / Schunkert, Heribert / Anonymous2810776 / Anonymous2820776 / Anonymous2830776 / Anonymous2840776. ·From the Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität, Munich, Germany (M.D., R. Malik) · Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.) · Institut für Medizinische Biometrie und Statistik (I.R.K.), and Institut für integrative und experimentelle Genomik (J.E.), Universität zu Lübeck, Lübeck, Germany · Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Germany (I.R.K.) · Department of Neurology and Center for Human Genetic Research (J.R.), and Cardiology Division (C.J.O.D.), Massachusetts General Hospital, Boston · Harvard Medical School, Boston, MA (J.R.) · Program in Medical and Population Genetics (J.R.), and Program in Medical and Population Genetics (S.K.), Broad Institute of Harvard and MIT, Cambridge, MA · Clinical Trial Service Unit and Epidemiological Studies Unit (R.C., J.C.H.), Wellcome Trust Centre for Human Genetics (H.W., M. Farrall), Department of Cardiovascular Medicine (M. Farrall), and Stroke Prevention Research Unit, Nuffield Department of Clinical Neuroscience (P.M.R.), John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom · deCODE Genetics, Reykjavik, Iceland (S.G., G.T., U.T., K.S.) · Department of Medicine, University of Maryland School of Medicine, Baltimore (B.D.M.) · Department of Medicine, Stanford University School of Medicine, Stanford, CA (T.L.A.) · Center for Translational Neuroscience and Mental Health Research, University of Newcastle, New South Wales, Australia (C.L.) · Hunter Medical Research Institute, New South Wales, Australia (C.L.) · National Heart, Lung and Blood Institute and NHLBI's Framingham Heart Study, MA (C.J.O.D., S.S.) · University of Texas Health Science Center at Houston (M. Fornage) · Cardiovascular Health Research Unit, Department of Epidemiology (B.M.P.), Department of Medicine (B.M.P.), Department of Health Services (B.M.P.), and Cardiovascular Health Research Unit, Department of Medicine (J.C.B.), University ·Stroke · Pubmed #24262325.

ABSTRACT: BACKGROUND AND PURPOSE: Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases. METHODS: Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genome-wide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance (P<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2167 individuals with the ischemic large artery stroke (LAS) subtype. RESULTS: Common variants associated with CAD at P<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, 3 and 5 loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (P<5×10(-8)) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Because these loci had prior evidence for genome-wide significance for CAD, we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (PIS=1.62×10(-7)) and ABO (PIS=2.6×10(-4)), as well as at HDAC9 (PLAS=2.32×10(-12)), 9p21 (PLAS=3.70×10(-6)), RAI1-PEMT-RASD1 (PLAS=2.69×10(-5)), EDNRA (PLAS=7.29×10(-4)), and CYP17A1-CNNM2-NT5C2 (PLAS=4.9×10(-4)). CONCLUSIONS: Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.

5 Clinical Trial Susceptibility Loci for Clinical Coronary Artery Disease and Subclinical Coronary Atherosclerosis Throughout the Life-Course. 2015

Salfati, Elias / Nandkeolyar, Shuktika / Fortmann, Stephen P / Sidney, Stephen / Hlatky, Mark A / Quertermous, Thomas / Go, Alan S / Iribarren, Carlos / Herrington, David M / Goldstein, Benjamin A / Assimes, Themistocles L. ·From the Department of Medicine, Stanford University School of Medicine, CA (E.S., S.P.F., M.A.H., T.Q., B.A.G., T.L.A.) · Ecole Doctorale B2T, IUH, Université Paris 7, Paris, France (E.S.) · Medical College of Wisconsin, Milwaukee (S.N.) · Kaiser Permanente Center for Health Research, Portland, OR (S.P.F.) · Kaiser Permanente Division of Research, Oakland, CA (S.S., A.S.G., C.I.) · Heart and Vascular Center of Excellence, Wake Forest School of Medicine, Winston-Salem, NC (D.M.H.) · and Department of Biostatistics and Bioinformatics, Duke University, Durham, NC (B.A.G.). ·Circ Cardiovasc Genet · Pubmed #26417035.

ABSTRACT: BACKGROUND: Recent genome-wide association studies have identified 49 single nucleotide polymorphisms associated with clinical coronary artery disease. The mechanism by which these loci influence risk remains largely unclear. METHODS AND RESULTS: We examined the association between a genetic risk score composed of high-risk alleles at the 49 single nucleotide polymorphisms and the degree of subclinical coronary atherosclerosis in 7798 participants from 6 studies stratified into 4 age groups at the time of assessment (15-34, 35-54, 55-74, and >75 years). Atherosclerosis was quantified by staining and direct visual inspection of the right coronary artery in the youngest group and by scanning for coronary artery calcification in the remaining groups. We defined cases as subjects within the top quartile of degree of atherosclerosis in 3 groups and as subjects with a coronary artery calcium score >0 in the fourth (35-54 years) where less than one quarter had any coronary artery calcium. In our meta-analysis of all strata, we found 1-SD increase in the genetic risk score increased the risk of advanced subclinical coronary atherosclerosis by 36% (P=8.3×10(-25)). This increase in risk was significant in all 4 age groups including the youngest group where atherosclerosis consisted primarily of raised lesions without macroscopic evidence of plaque rupture or thrombosis. Results were similar when we restricted the genetic risk score to 32 single nucleotide polymorphisms not associated with traditional risk factors or when we adjusted for traditional risk factors. CONCLUSIONS: A genetic risk score for clinical coronary artery disease is associated with advanced subclinical coronary atherosclerosis throughout the life-course. This association is apparent even at the earliest, uncomplicated stages of atherosclerosis.

6 Article Exome-wide association study of plasma lipids in >300,000 individuals. 2017

Liu, Dajiang J / Peloso, Gina M / Yu, Haojie / Butterworth, Adam S / Wang, Xiao / Mahajan, Anubha / Saleheen, Danish / Emdin, Connor / Alam, Dewan / Alves, Alexessander Couto / Amouyel, Philippe / Di Angelantonio, Emanuele / Arveiler, Dominique / Assimes, Themistocles L / Auer, Paul L / Baber, Usman / Ballantyne, Christie M / Bang, Lia E / Benn, Marianne / Bis, Joshua C / Boehnke, Michael / Boerwinkle, Eric / Bork-Jensen, Jette / Bottinger, Erwin P / Brandslund, Ivan / Brown, Morris / Busonero, Fabio / Caulfield, Mark J / Chambers, John C / Chasman, Daniel I / Chen, Y Eugene / Chen, Yii-Der Ida / Chowdhury, Rajiv / Christensen, Cramer / Chu, Audrey Y / Connell, John M / Cucca, Francesco / Cupples, L Adrienne / Damrauer, Scott M / Davies, Gail / Deary, Ian J / Dedoussis, George / Denny, Joshua C / Dominiczak, Anna / Dubé, Marie-Pierre / Ebeling, Tapani / Eiriksdottir, Gudny / Esko, Tõnu / Farmaki, Aliki-Eleni / Feitosa, Mary F / Ferrario, Marco / Ferrieres, Jean / Ford, Ian / Fornage, Myriam / Franks, Paul W / Frayling, Timothy M / Frikke-Schmidt, Ruth / Fritsche, Lars G / Frossard, Philippe / Fuster, Valentin / Ganesh, Santhi K / Gao, Wei / Garcia, Melissa E / Gieger, Christian / Giulianini, Franco / Goodarzi, Mark O / Grallert, Harald / Grarup, Niels / Groop, Leif / Grove, Megan L / Gudnason, Vilmundur / Hansen, Torben / Harris, Tamara B / Hayward, Caroline / Hirschhorn, Joel N / Holmen, Oddgeir L / Huffman, Jennifer / Huo, Yong / Hveem, Kristian / Jabeen, Sehrish / Jackson, Anne U / Jakobsdottir, Johanna / Jarvelin, Marjo-Riitta / Jensen, Gorm B / Jørgensen, Marit E / Jukema, J Wouter / Justesen, Johanne M / Kamstrup, Pia R / Kanoni, Stavroula / Karpe, Fredrik / Kee, Frank / Khera, Amit V / Klarin, Derek / Koistinen, Heikki A / Kooner, Jaspal S / Kooperberg, Charles / Kuulasmaa, Kari / Kuusisto, Johanna / Laakso, Markku / Lakka, Timo / Langenberg, Claudia / Langsted, Anne / Launer, Lenore J / Lauritzen, Torsten / Liewald, David C M / Lin, Li An / Linneberg, Allan / Loos, Ruth J F / Lu, Yingchang / Lu, Xiangfeng / Mägi, Reedik / Malarstig, Anders / Manichaikul, Ani / Manning, Alisa K / Mäntyselkä, Pekka / Marouli, Eirini / Masca, Nicholas G D / Maschio, Andrea / Meigs, James B / Melander, Olle / Metspalu, Andres / Morris, Andrew P / Morrison, Alanna C / Mulas, Antonella / Müller-Nurasyid, Martina / Munroe, Patricia B / Neville, Matt J / Nielsen, Jonas B / Nielsen, Sune F / Nordestgaard, Børge G / Ordovas, Jose M / Mehran, Roxana / O'Donnell, Christoper J / Orho-Melander, Marju / Molony, Cliona M / Muntendam, Pieter / Padmanabhan, Sandosh / Palmer, Colin N A / Pasko, Dorota / Patel, Aniruddh P / Pedersen, Oluf / Perola, Markus / Peters, Annette / Pisinger, Charlotta / Pistis, Giorgio / Polasek, Ozren / Poulter, Neil / Psaty, Bruce M / Rader, Daniel J / Rasheed, Asif / Rauramaa, Rainer / Reilly, Dermot F / Reiner, Alex P / Renström, Frida / Rich, Stephen S / Ridker, Paul M / Rioux, John D / Robertson, Neil R / Roden, Dan M / Rotter, Jerome I / Rudan, Igor / Salomaa, Veikko / Samani, Nilesh J / Sanna, Serena / Sattar, Naveed / Schmidt, Ellen M / Scott, Robert A / Sever, Peter / Sevilla, Raquel S / Shaffer, Christian M / Sim, Xueling / Sivapalaratnam, Suthesh / Small, Kerrin S / Smith, Albert V / Smith, Blair H / Somayajula, Sangeetha / Southam, Lorraine / Spector, Timothy D / Speliotes, Elizabeth K / Starr, John M / Stirrups, Kathleen E / Stitziel, Nathan / Strauch, Konstantin / Stringham, Heather M / Surendran, Praveen / Tada, Hayato / Tall, Alan R / Tang, Hua / Tardif, Jean-Claude / Taylor, Kent D / Trompet, Stella / Tsao, Philip S / Tuomilehto, Jaakko / Tybjaerg-Hansen, Anne / van Zuydam, Natalie R / Varbo, Anette / Varga, Tibor V / Virtamo, Jarmo / Waldenberger, Melanie / Wang, Nan / Wareham, Nick J / Warren, Helen R / Weeke, Peter E / Weinstock, Joshua / Wessel, Jennifer / Wilson, James G / Wilson, Peter W F / Xu, Ming / Yaghootkar, Hanieh / Young, Robin / Zeggini, Eleftheria / Zhang, He / Zheng, Neil S / Zhang, Weihua / Zhang, Yan / Zhou, Wei / Zhou, Yanhua / Zoledziewska, Magdalena / Anonymous821322 / Anonymous831322 / Anonymous841322 / Anonymous851322 / Anonymous861322 / Howson, Joanna M M / Danesh, John / McCarthy, Mark I / Cowan, Chad A / Abecasis, Goncalo / Deloukas, Panos / Musunuru, Kiran / Willer, Cristen J / Kathiresan, Sekar. ·Department of Public Health Sciences, Institute of Personalized Medicine, Penn State College of Medicine, Hershey, Pennsylvania, USA. · Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA. · Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA. · Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA. · MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. · The National Institute for Health Research Blood and Transplant Research Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge, Cambridge, UK. · Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. · Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Center for Non-Communicable Diseases, Karachi, Pakistan. · Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. · ICDDR, B, Dhaka, Bangladesh. · Imperial College London, London, UK. · Université Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE-Risk Factors and Molecular Determinants of Aging-related Diseases, Lille, France. · Department of Epidemiology and Public Health, EA 3430, University of Strasbourg, Strasbourg, France. · VA Palo Alto Health Care System, Palo Alto, California, USA. · Department of Medicine, Stanford University School of Medicine, Stanford, California, USA. · Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, USA. · Cardiovascular Institute, Mount Sinai Medical Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Department of Medicine, Baylor College of Medicine, Houston, Texas, USA. · Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. · Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark. · Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. · Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA. · Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA. · Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA. · Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA. · The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. · The Charles Bronfman Institute for Personalized Medicine, Ichan School of Medicine at Mount Sinai, New York, New York, USA. · Department of Clinical Biochemistry, Lillebaelt Hospital, Vejle, Denmark. · Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark. · Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. · Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Cagliari, Italy. · The Barts Heart Centre, William Harvey Research Institute, Queen Mary University of London, London, UK. · NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, UK. · Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK. · Department of Cardiology, Ealing Hospital NHS Trust, Southall, UK. · Imperial College Healthcare NHS Trust, London, UK. · Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. · Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. · Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, USA. · The Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Departments of Pediatrics and Medicine, Los Angeles, California, USA. · Medical Department, Lillebaelt Hospital, Vejle, Denmark. · NHLBI Framingham Heart Study, Framingham, Massachusetts, USA. · Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK. · Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, Sassari, Italy. · Corporal Michael Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA. · Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK. · Department of Psychology, University of Edinburgh, Edinburgh, UK. · Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece. · Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA. · Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA. · British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. · Montreal Heart Institute, Montreal, Quebec, Canada. · Université de Montréal Beaulieu-Saucier Pharmacogenomics Center, Montreal, Quebec, Canada. · Université de Montréal, Montreal, Quebec, Canada. · Department of Medicine, Oulu University Hospital and University of Oulu, Oulu, Finland. · The Icelandic Heart Association, Kopavogur, Iceland. · Estonian Genome Center, University of Tartu, Tartu, Estonia. · Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA. · Research Centre in Epidemiology and Preventive Medicine-EPIMED, Department of Medicine and Surgery, University of Insubria, Varese, Italy. · Department of Epidemiology, UMR 1027-INSERM, Toulouse University-CHU Toulouse, Toulouse, France. · Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK. · Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, Texas, USA. · Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden. · Department of Public Health & Clinical Medicine, Umeå University, Umeå, Sweden. · Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA. · Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK. · Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain. · Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA. · Department of Cardiology, Peking University Third Hospital, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Beijing, China. · National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA. · German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany. · Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. · Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. · Departments of Medicine and of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA. · Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, California, USA. · Department of Clinical Sciences, Diabetes and Endocrinology, Clinical Research Centre, Lund University, Malmö, Sweden. · Faculty of Medicine, University of Iceland, Reykjavik, Iceland. · Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark. · Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, Maryland, USA. · Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. · Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts, USA. · Department of Public Health and General Practice, HUNT Research Centre, Norwegian University of Science and Technology, Levanger, Norway. · St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway. · Department of Cardiology, Peking University First Hospital, Beijing, China. · K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway. · Department of Health Sciences, University of Iceland, Reykjavik, Iceland. · The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen, Denmark. · Steno Diabetes Center, Gentofte, Denmark. · National Institute of Public Health, Southern Denmark University, Copenhagen, Denmark. · Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands. · The Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands. · Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark. · William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. · Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. · Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK. · UKCRC Centre of Excellence for Public Health, Queens University, Belfast, UK. · Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, Massachusetts, USA. · Department of Health, National Institute for Health and Welfare, Helsinki, Finland. · Department of Medicine and Abdominal Center: Endocrinology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. · Minerva Foundation Institute for Medical Research, Helsinki, Finland. · National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, London, UK. · Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. · Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland. · Department of Physiology, Institute of Biomedicine, University of Eastern Finland, Kuopio Campus, Kuopio, Finland. · Kuopio Research Institute of Exercise Medicine, Kuopio, Finland. · Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland. · MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK. · Faculty of Health and Medical Sciences, University of Denmark, Copenhagen, Denmark. · Department of Public Health, Section of General Practice, University of Aarhus, Aarhus, Denmark. · Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark. · Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. · Research Center for Prevention and Health, Copenhagen, Denmark. · The Mindich Child Health and Development Institute, Ichan School of Medicine at Mount Sinai, New York, New York, USA. · State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. · Cardiovascular Genetics and Genomics Group, Cardiovascular Medicine Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden. · Pharmatherapeutics Clinical Research, Pfizer Worldwide R&D, Sollentuna, Sweden. · Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA. · Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. · Unit of Primary Health Care, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland. · Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. · NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK. · Division of General Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. · Department of Clinical Sciences, University Hospital Malmo Clinical Research Center, Lund University, Malmo, Sweden. · Department of Biostatistics, University of Liverpool, Liverpool, UK. · Department of Medicine I, Ludwig-Maximilians-University, Munich, Germany. · DZHK German Centre for Cardiovascular Research, Munich Heart Alliance, Munich, Germany. · Department of Cardiovascular Epidemiology and Population Genetics, National Center for Cardiovascular Investigation, Madrid, Spain. · IMDEA-Alimentacion, Madrid, Spain. · Nutrition and Genomics Laboratory, Jean Mayer-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, USA. · Genetics, Merck Sharp & Dohme Corporation, Kenilworth, New Jersey, USA. · G3 Pharmaceuticals, Lexington, Massachusetts, USA. · Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. · Institute of Molecular Medicine FIMM, University of Helsinki, Finland. · Faculty of Medicine, University of Split, Split, Croatia. · Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK. · International Centre for Circulatory Health, Imperial College London, London, UK. · Kaiser Permanente Washington Health Research Institute, Seattle, Washington, USA. · Departments of Epidemiology and Health Services, University of Washington, Seattle, Washington, USA. · Departments of Genetics, Medicine, and Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Department of Epidemiology, University of Washington, Seattle, Washington, USA. · Department of Biobank Research, Umeå University, Umeå, Sweden. · Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA. · Imaging, Merck Sharp & Dohme Corporation, Kenilworth, New Jersey, USA. · Saw Swee Hock School of Public Health, National University of Singapore, Singapore. · Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. · Department of Twin Research and Genetic Epidemiology, King's College London, London, UK. · Division of Population Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK. · Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK. · Scientific Informatics, Merck Sharp & Dohme Corporation, Kenilworth, New Jersey, USA. · Wellcome Trust Sanger Institute, Genome Campus, Hinxton, UK. · Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA. · Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK. · Department of Haematology, University of Cambridge, Cambridge, UK. · Cardiovascular Division, Departments of Medicine and Genetics, Washington University School of Medicine, St. Louis, Missouri, USA. · The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri, USA. · IBE, Faculty of Medicine, Ludwig-Maximilians-Universität Munich, Germany. · Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. · Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan. · Department of Medicine, Division of Molecular Medicine, Columbia University, New York, New York, USA. · Department of Genetics, Stanford University School of Medicine, Stanford, California, USA. · Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands. · Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland. · Dasman Diabetes Institute, Dasman, Kuwait. · Centre for Vascular Prevention, Danube-University Krems, Krems, Austria. · Saudi Diabetes Research Group, King Abdulaziz University, Fahd Medical Research Center, Jeddah, Saudi Arabia. · The Heart Centre, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. · Department of Epidemiology, Indiana University Fairbanks School of Public Health, Indianapolis, Indiana, USA. · Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA. · Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA. · Atlanta VA Medical Center, Decatur, Georgia, USA. · Emory Clinical Cardiovascular Research Institute, Atlanta, Georgia, USA. · Department of Cardiology, Institute of Vascular Medicine, Peking University Third Hospital, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China. · Yale College, Yale University, New Haven, Connecticut, USA. · Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. · Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia. ·Nat Genet · Pubmed #29083408.

ABSTRACT: We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

7 Article Association analyses based on false discovery rate implicate new loci for coronary artery disease. 2017

Nelson, Christopher P / Goel, Anuj / Butterworth, Adam S / Kanoni, Stavroula / Webb, Tom R / Marouli, Eirini / Zeng, Lingyao / Ntalla, Ioanna / Lai, Florence Y / Hopewell, Jemma C / Giannakopoulou, Olga / Jiang, Tao / Hamby, Stephen E / Di Angelantonio, Emanuele / Assimes, Themistocles L / Bottinger, Erwin P / Chambers, John C / Clarke, Robert / Palmer, Colin N A / Cubbon, Richard M / Ellinor, Patrick / Ermel, Raili / Evangelou, Evangelos / Franks, Paul W / Grace, Christopher / Gu, Dongfeng / Hingorani, Aroon D / Howson, Joanna M M / Ingelsson, Erik / Kastrati, Adnan / Kessler, Thorsten / Kyriakou, Theodosios / Lehtimäki, Terho / Lu, Xiangfeng / Lu, Yingchang / März, Winfried / McPherson, Ruth / Metspalu, Andres / Pujades-Rodriguez, Mar / Ruusalepp, Arno / Schadt, Eric E / Schmidt, Amand F / Sweeting, Michael J / Zalloua, Pierre A / AlGhalayini, Kamal / Keavney, Bernard D / Kooner, Jaspal S / Loos, Ruth J F / Patel, Riyaz S / Rutter, Martin K / Tomaszewski, Maciej / Tzoulaki, Ioanna / Zeggini, Eleftheria / Erdmann, Jeanette / Dedoussis, George / Björkegren, Johan L M / Anonymous3681104 / Anonymous3691104 / Anonymous3701104 / Schunkert, Heribert / Farrall, Martin / Danesh, John / Samani, Nilesh J / Watkins, Hugh / Deloukas, Panos. ·Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. · National Institute for Health Research Leicester Biomedical Research Centre, Leicester, UK. · Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. · Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. · MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. · NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. · William Harvey Research Institute, Barts &the London Medical School, Queen Mary University of London, London, UK. · Centre for Genomic Health, Queen Mary University of London, London, UK. · German Heart Center Munich, Clinic at Technische Universität München and Deutsches Zentrum für Herz- und Kreislauferkrankungen (DZHK), partner site Munich Heart Alliance, Munich, Germany. · CTSU, Nuffield Department of Population Health, University of Oxford, Oxford, UK. · Department of Medicine, Stanford University School of Medicine, Stanford, California, USA. · Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Department of Epidemiology and Biostatistics, Imperial College London, London, UK. · Department of Cardiology, Ealing Hospital, London North West Healthcare NHS Trust, Southall, UK. · Imperial College Healthcare NHS Trust, London, UK. · Molecular and Clinical Medicine, Biomedical Research Institute, University of Dundee, Ninewells Hospital, Dundee, UK. · Pharmacogenomics Centre, Biomedical Research Institute, University of Dundee, Ninewells Hospital, Dundee, UK. · Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK. · Cardiac Arrhythmia Service and Cardiovascular Research Center, Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, Massachusetts, USA. · Department of Cardiac Surgery, Tartu University Hospital, Tartu, Estonia. · Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece. · Department of Clinical Sciences, Genetic &Molecular Epidemiology Unit, Lund University Diabetes Center, Skåne University Hospital, Lund University, Malmö, Sweden. · Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA. · Department of Public Health and Clinical Medicine, Unit of Medicine, Umeå University, Umeå, Sweden. · State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. · Institute of Cardiovascular Science, University College London,London, UK. · Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA. · Department of Clinical Chemistry, Fimlab Laboratories and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland. · Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. · Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria. · Medical Clinic V (Nephrology, Rheumatology, Hypertensiology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. · Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany. · Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada. · Estonian Genome Center, University of Tartu, Tartu, Estonia. · Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, UK. · Clinical Gene Networks AB, Stockholm, Sweden. · Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Lebanese American University, School of Medicine, Beirut, Lebanon. · Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. · Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia. · Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. · Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK. · Cardiovascular Science, National Heart and Lung Institute, Imperial College London, London, UK. · Mindich Child Health Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Farr Institute of Health Informatics, UCL, London, UK. · Bart's Heart Centre, St Bartholomew's Hospital, London, UK. · Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. · Manchester Diabetes Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK. · Division of Medicine, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK. · Wellcome Trust Sanger Institute, Hinxton, UK. · Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany. · DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany. · University Heart Center Lübeck, Lübeck, Germany. · Department of Nutrition-Dietetics, Harokopio University, Athens, Greece. · Integrated Cardio Metabolic Centre, Department of Medicine, Karolinska Institutet, Karolinska Universitetssjukhuset, Huddinge, Sweden. · Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK. · Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia. ·Nat Genet · Pubmed #28714975.

ABSTRACT: Genome-wide association studies (GWAS) in coronary artery disease (CAD) had identified 66 loci at 'genome-wide significance' (P < 5 × 10

8 Article Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms. 2017

Howson, Joanna M M / Zhao, Wei / Barnes, Daniel R / Ho, Weang-Kee / Young, Robin / Paul, Dirk S / Waite, Lindsay L / Freitag, Daniel F / Fauman, Eric B / Salfati, Elias L / Sun, Benjamin B / Eicher, John D / Johnson, Andrew D / Sheu, Wayne H H / Nielsen, Sune F / Lin, Wei-Yu / Surendran, Praveen / Malarstig, Anders / Wilk, Jemma B / Tybjærg-Hansen, Anne / Rasmussen, Katrine L / Kamstrup, Pia R / Deloukas, Panos / Erdmann, Jeanette / Kathiresan, Sekar / Samani, Nilesh J / Schunkert, Heribert / Watkins, Hugh / Anonymous2140907 / Do, Ron / Rader, Daniel J / Johnson, Julie A / Hazen, Stanley L / Quyyumi, Arshed A / Spertus, John A / Pepine, Carl J / Franceschini, Nora / Justice, Anne / Reiner, Alex P / Buyske, Steven / Hindorff, Lucia A / Carty, Cara L / North, Kari E / Kooperberg, Charles / Boerwinkle, Eric / Young, Kristin / Graff, Mariaelisa / Peters, Ulrike / Absher, Devin / Hsiung, Chao A / Lee, Wen-Jane / Taylor, Kent D / Chen, Ying-Hsiang / Lee, I-Te / Guo, Xiuqing / Chung, Ren-Hua / Hung, Yi-Jen / Rotter, Jerome I / Juang, Jyh-Ming J / Quertermous, Thomas / Wang, Tzung-Dau / Rasheed, Asif / Frossard, Philippe / Alam, Dewan S / Majumder, Abdulla Al Shafi / Di Angelantonio, Emanuele / Chowdhury, Rajiv / Anonymous2150907 / Chen, Yii-Der Ida / Nordestgaard, Børge G / Assimes, Themistocles L / Danesh, John / Butterworth, Adam S / Saleheen, Danish. ·MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. · Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Department of Applied Mathematics, University of Nottingham Malaysia Campus, Semenyih, Malaysia. · Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK. · HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA. · Pfizer Worldwide Research and Development, Cambridge, Massachusetts, USA. · Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, California, USA. · Stanford Cardiovascular Institute, Stanford University, Stanford, California, USA. · National Heart, Lung, and Blood Institute, Population Sciences Branch, Bethesda, Maryland, USA. · NHLBI and Boston University's The Framingham Heart Study, Framingham, Massachusetts, USA. · Division of Endocrine and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan. · School of Medicine, National Yang-Ming University, Taipei, Taiwan. · College of Medicine, National Defense Medical Center, Taipei, Taiwan. · Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark. · Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK. · Pfizer Worldwide Research and Development, Stockholm, Sweden. · Pfizer Worldwide Research and Development, Human Genetics, Cambridge, Massachusetts, USA. · Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. · Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. · William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. · Centre for Genomic Health, Queen Mary University of London, London, UK. · Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany. · DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany. · University Heart Center Lübeck, Lübeck, Germany. · Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. · Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. · Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. · NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK. · Deutsches Herzzentrum München, Technische Universität München, Munich, Germany. · DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany. · Radcliffe Department of Medicine, University of Oxford, Oxford, UK. · Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. · Charles Bronfman Institute for Personalized Medicine, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Departments of Genetics, Medicine, and Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · University of Florida College of Pharmacy, Gainesville, Florida, USA. · Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland, Ohio, USA. · Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia, USA. · Saint Luke's Mid America Heart Institute, Kansas City, Missouri, USA. · Department of Biomedical and Health Informatics, University of Missouri-Kansas City, Kansas City, Missouri, USA. · College of Medicine, University of Florida, Gainesville, Florida, USA. · Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA. · Department of Epidemiology, University of Washington, Seattle, Washington, USA. · Department of Statistics and Biostatistics, Rutgers University, Piscataway, New Jersey, USA. · Division of Genomic Medicine, National Human Genome Research Institute, US National Institutes of Health, Bethesda,Maryland, USA. · Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. · Carolina Center for Genome Sciences, Chapel Hill, North Carolina, USA. · Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA. · Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA. · Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan. · Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan. · Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, California, USA. · School of Medicine, Chung Shan Medical University, Taichung, Taiwan. · Division of Endocrinology and Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. · Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, LABioMed at Harbor-UCLA Medical Center, Torrance, California, USA. · Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. · National Taiwan University College of Medicine, Taipei, Taiwan. · Centre for Non-Communicable Disease, Karachi, Pakistan. · School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada. · National Institute of Cardiovascular Diseases, Sher-e-Bangla Nagar, Bangladesh. · National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK. · Wellcome Trust Sanger Institute, Hinxton, UK. · British Heart Foundation Cambridge Centre of Excellence, Department of Medicine, University of Cambridge, Cambridge, UK. ·Nat Genet · Pubmed #28530674.

ABSTRACT: Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10

9 Article Associations between a Genetic Risk Score for Clinical CAD and Early Stage Lesions in the Coronary Artery and the Aorta. 2016

Salfati, Elias L / Herrington, David M / Assimes, Themistocles L. ·Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, United States of America. · Stanford Cardiovascular Institute, Stanford University, Stanford, California, United States of America. · Wake Forest University Baptist Medical Center, Medical Center Boulevard, Winston-Salem, North Carolina 27157, United States of America. ·PLoS One · Pubmed #27861582.

ABSTRACT: OBJECTIVE: The correlation between the extent of fatty streaks, more advanced atherosclerotic lesions, and community rates of coronary artery disease (CAD) is substantially higher for the coronary artery compared to the aorta. We sought to determine whether a genetic basis contributes to these differences. APPROACH AND RESULTS: We conducted a cluster analysis of 6 subclinical atherosclerosis phenotypes documented in 564 white participants of the Pathobiological Determinants of Atherosclerosis in Youth study including the extent of fatty streaks and raised lesions in the coronary artery (CF and CR), thoracic aorta (TF and TR), and abdominal aorta (AF and AR) followed by a genetic association analysis of the same phenotypes. Our cluster analysis grouped all raised lesions and fatty streaks in the coronary into one cluster (CF, CR, TR, and AR) and the fatty streaks in the aorta into a second cluster (TF and AF). We found a genetic risk score of high-risk alleles at 57 susceptibility loci for CAD to be variably associated with the phenotypes in the first cluster (OR: 1.30 p = 0.009 for being in top quartile of degree of involvement of CF, 1.34 p = 0.005 for CR, 1.25: p = 0.11 for TR, and 1.19 p = 0.08 for AR) but not at all with the phenotypes in the second cluster (OR: 1.01, p = 0.95 for TF and 0.98, p = 0.82 for AF). CONCLUSIONS: The genetic determinants of fatty streaks in the aorta do not appear to overlap substantially with the genetic determinants of fatty streaks in the coronary as well as raised lesions in both the coronary and the aorta. These findings may explain why a larger fraction of fatty streaks in the aorta are less likely to progress to raised lesions compared to the coronary artery.

10 Article No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis. 2016

Loley, Christina / Alver, Maris / Assimes, Themistocles L / Bjonnes, Andrew / Goel, Anuj / Gustafsson, Stefan / Hernesniemi, Jussi / Hopewell, Jemma C / Kanoni, Stavroula / Kleber, Marcus E / Lau, King Wai / Lu, Yingchang / Lyytikäinen, Leo-Pekka / Nelson, Christopher P / Nikpay, Majid / Qu, Liming / Salfati, Elias / Scholz, Markus / Tukiainen, Taru / Willenborg, Christina / Won, Hong-Hee / Zeng, Lingyao / Zhang, Weihua / Anand, Sonia S / Beutner, Frank / Bottinger, Erwin P / Clarke, Robert / Dedoussis, George / Do, Ron / Esko, Tõnu / Eskola, Markku / Farrall, Martin / Gauguier, Dominique / Giedraitis, Vilmantas / Granger, Christopher B / Hall, Alistair S / Hamsten, Anders / Hazen, Stanley L / Huang, Jie / Kähönen, Mika / Kyriakou, Theodosios / Laaksonen, Reijo / Lind, Lars / Lindgren, Cecilia / Magnusson, Patrik K E / Marouli, Eirini / Mihailov, Evelin / Morris, Andrew P / Nikus, Kjell / Pedersen, Nancy / Rallidis, Loukianos / Salomaa, Veikko / Shah, Svati H / Stewart, Alexandre F R / Thompson, John R / Zalloua, Pierre A / Chambers, John C / Collins, Rory / Ingelsson, Erik / Iribarren, Carlos / Karhunen, Pekka J / Kooner, Jaspal S / Lehtimäki, Terho / Loos, Ruth J F / März, Winfried / McPherson, Ruth / Metspalu, Andres / Reilly, Muredach P / Ripatti, Samuli / Sanghera, Dharambir K / Thiery, Joachim / Watkins, Hugh / Deloukas, Panos / Kathiresan, Sekar / Samani, Nilesh J / Schunkert, Heribert / Erdmann, Jeanette / König, Inke R. ·Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Germany. · DZHK (German Centre for Cardiovascular Research), partner site Hamburg-Lübeck-Kiel, Lübeck, Germany. · Estonian Genome Center, University of Tartu, Tartu, Estonia. · Institute of Molecular and Cell Biology, Tartu, Estonia. · Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine Stanford, Standford, California, USA. · Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. · Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. · Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. · Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. · Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland. · Department of Cardiology, Heart Hospital and University of Tampere School of Medicine, Tampere, Finland. · CTSU, Nuffield Department of Population Health, University of Oxford, Oxford, UK. · William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. · Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. · The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, USA. · Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland. · Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. · NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK. · Ruddy Canadian Cardiovascular Genetics Centre University of Ottawa Heart Institute, Ottawa, Canada. · Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Institute for Medical Informatics, Statistics and Epidemiology/Medical Faculty/University of Leipzig, Leipzig, Germany. · LIFE Research Center of Civilization Diseases, Leipzig, Germany. · Analytic and Translation Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA. · Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA. · Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Germany and University Heart Center Luebeck, Campus Lübeck, Lübeck, Germany. · Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Samsung Medical Center, Seoul, Korea. · Deutsches Herzzentrum München, Technische Universität München, Munich, Germany. · DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, München, Germany. · Department of Epidemiology and Biostatistics, Imperial College London, London, UK. · Department of Cardiology, Ealing Hospital National Health Service (NHS) Trust, Middlesex, UK. · Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada. · Heart Center Leipzig, Cardiology, University of Leipzig, Leipzig, Germany. · Harokopio University Athens, Athens, Greece. · The Center for Statistical Genetics, Icahn School of Medicine at Mount Sinai, New York, USA. · The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, USA. · The Zena and Michael A. Weiner Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, USA. · Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. · INSERM, UMRS1138, Centre de Recherche des Cordeliers, Paris, France. · Department of Public Health and Caring Sciences, Geriatrics, Uppsala Universit, Uppsala, Sweden. · Duke University School of Medicine, Durham, North Carolina, USA. · Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, UK. · Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden. · Cleveland Clinic, Cleveland, Ohio, USA. · Boston VA Research Institute, Inc., Boston, Massachusetts, USA. · Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland. · Department of Clinical Physiology, University of Tampere School of Medicine, Tampere, Finland. · Zora Biosciences, Espoo, Finland. · Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden. · Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA. · Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. · Department of Biostatistics, University of Liverpool, Liverpool, UK. · Second Department of Cardiology, University General Hospital Attikon, Athens, Greece. · Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland. · Department of Health Sciences, University of Leicester, Leicester, UK. · Lebanese American University, School of Medicine, Beirut, Lebanon. · Harvard School of Public Health, Boston, Massachusetts, USA. · Imperial College Healthcare NHS Trust, London, UK. · Kaiser Permanente, Division of Research, Oakland, California, USA. · Department of Forensic Medicine, University of Tampere School of Medicine, Tampere, Finland. · Cardiovascular Science, National Heart and Lung Institute, Imperial College London, London, UK. · The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, USA. · Synlab Academy, Synlab Services GmbH, Mannheim, Germany. · Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria. · Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Hjelt Institute, University of Helsinki, Helsinki, Finland. · Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland. · Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. · Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. · Oklahoma Center for Neuroscience, Oklahoma City, Oklahoma, USA. · Institute for Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Medical Faculty, Leipzig, Germany. · Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. · Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia. · Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. ·Sci Rep · Pubmed #27731410.

ABSTRACT: In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD.

11 Article Integrative functional genomics identifies regulatory mechanisms at coronary artery disease loci. 2016

Miller, Clint L / Pjanic, Milos / Wang, Ting / Nguyen, Trieu / Cohain, Ariella / Lee, Jonathan D / Perisic, Ljubica / Hedin, Ulf / Kundu, Ramendra K / Majmudar, Deshna / Kim, Juyong B / Wang, Oliver / Betsholtz, Christer / Ruusalepp, Arno / Franzén, Oscar / Assimes, Themistocles L / Montgomery, Stephen B / Schadt, Eric E / Björkegren, Johan L M / Quertermous, Thomas. ·Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California 94305, USA. · Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA. · Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA. · Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm SE-171 77, Sweden. · Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala SE-751 05, Sweden. · Department of Medical Biochemistry and Biophysics, Vascular Biology Unit, Karolinska Institutet, Stockholm SE-171 77, Sweden. · Department of Cardiac Surgery, Tartu University Hospital, Tartu 50406, Estonia. · Clinical Gene Networks AB, Stockholm SE-114 44, Sweden. · Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA. · Department of Physiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Tartu 50406, Estonia. ·Nat Commun · Pubmed #27386823.

ABSTRACT: Coronary artery disease (CAD) is the leading cause of mortality and morbidity, driven by both genetic and environmental risk factors. Meta-analyses of genome-wide association studies have identified >150 loci associated with CAD and myocardial infarction susceptibility in humans. A majority of these variants reside in non-coding regions and are co-inherited with hundreds of candidate regulatory variants, presenting a challenge to elucidate their functions. Herein, we use integrative genomic, epigenomic and transcriptomic profiling of perturbed human coronary artery smooth muscle cells and tissues to begin to identify causal regulatory variation and mechanisms responsible for CAD associations. Using these genome-wide maps, we prioritize 64 candidate variants and perform allele-specific binding and expression analyses at seven top candidate loci: 9p21.3, SMAD3, PDGFD, IL6R, BMP1, CCDC97/TGFB1 and LMOD1. We validate our findings in expression quantitative trait loci cohorts, which together reveal new links between CAD associations and regulatory function in the appropriate disease context.

12 Article Genetics of Coronary Artery Disease in Taiwan: A Cardiometabochip Study by the Taichi Consortium. 2016

Assimes, Themistocles L / Lee, I-T / Juang, Jyh-Ming / Guo, Xiuqing / Wang, Tzung-Dau / Kim, Eric T / Lee, Wen-Jane / Absher, Devin / Chiu, Yen-Feng / Hsu, Chih-Cheng / Chuang, Lee-Ming / Quertermous, Thomas / Hsiung, Chao A / Rotter, Jerome I / Sheu, Wayne H-H / Chen, Yii-Der Ida / Taylor, Kent D. ·Department of Medicine, Stanford University School of Medicine, Stanford, California, United States of America. · Division of Endocrine and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan. · Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, National University College of Medicine, Taipei, Taiwan. · Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, and Department of Pediatrics, University of California Los Angeles, Los Angeles, California, United States of America. · Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan. · HudsonAlpha Institute for Biotechnology, Huntsville, Alabama. · Institute of Population Health Sciences, Division of Biostatistics and Bioinformatics, National Health Research Institutes, Zhunan Town, Miaoli County, Taiwan. · Division of Endocrine and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. ·PLoS One · Pubmed #26982883.

ABSTRACT: By means of a combination of genome-wide and follow-up studies, recent large-scale association studies of populations of European descent have now identified over 46 loci associated with coronary artery disease (CAD). As part of the TAICHI Consortium, we have collected and genotyped 8556 subjects from Taiwan, comprising 5423 controls and 3133 cases with coronary artery disease, for 9087 CAD SNPs using the CardioMetaboChip. We applied penalized logistic regression to ascertain the top SNPs that contribute together to CAD susceptibility in Taiwan. We observed that the 9p21 locus contributes to CAD at the level of genome-wide significance (rs1537372, with the presence of C, the major allele, the effect estimate is -0.216, standard error 0.033, p value 5.8x10-10). In contrast to a previous report, we propose that the 9p21 locus is a single genetic contribution to CAD in Taiwan because: 1) the penalized logistic regression and the follow-up conditional analysis suggested that rs1537372 accounts for all of the CAD association in 9p21, and 2) the high linkage disequilibrium observed for all associated SNPs in 9p21. We also observed evidence for the following loci at a false discovery rate >5%: SH2B3, ADAMTS7, PHACTR1, GGCX, HTRA1, COL4A1, and LARP6-LRRC49. We also took advantage of the fact that penalized methods are an efficient approach to search for gene-by-gene interactions, and observed that two-way interactions between the PHACTR1 and ADAMTS7 loci and between the SH2B3 and COL4A1 loci contribute to CAD risk. Both the similarities and differences between the significance of these loci when compared with significance of loci in studies of populations of European descent underscore the fact that further genetic association of studies in additional populations will provide clues to identify the genetic architecture of CAD across all populations worldwide.

13 Article The glycolytic enzyme PKM2 bridges metabolic and inflammatory dysfunction in coronary artery disease. 2016

Shirai, Tsuyoshi / Nazarewicz, Rafal R / Wallis, Barbara B / Yanes, Rolando E / Watanabe, Ryu / Hilhorst, Marc / Tian, Lu / Harrison, David G / Giacomini, John C / Assimes, Themistocles L / Goronzy, Jörg J / Weyand, Cornelia M. ·Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305. · Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305 Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232. · Division of Biostatistics, Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA 94305. · Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232. · Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305. · Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305 cweyand@stanford.edu. ·J Exp Med · Pubmed #26926996.

ABSTRACT: Abnormal glucose metabolism and enhanced oxidative stress accelerate cardiovascular disease, a chronic inflammatory condition causing high morbidity and mortality. Here, we report that in monocytes and macrophages of patients with atherosclerotic coronary artery disease (CAD), overutilization of glucose promotes excessive and prolonged production of the cytokines IL-6 and IL-1β, driving systemic and tissue inflammation. In patient-derived monocytes and macrophages, increased glucose uptake and glycolytic flux fuel the generation of mitochondrial reactive oxygen species, which in turn promote dimerization of the glycolytic enzyme pyruvate kinase M2 (PKM2) and enable its nuclear translocation. Nuclear PKM2 functions as a protein kinase that phosphorylates the transcription factor STAT3, thus boosting IL-6 and IL-1β production. Reducing glycolysis, scavenging superoxide and enforcing PKM2 tetramerization correct the proinflammatory phenotype of CAD macrophages. In essence, PKM2 serves a previously unidentified role as a molecular integrator of metabolic dysfunction, oxidative stress and tissue inflammation and represents a novel therapeutic target in cardiovascular disease.

14 Article A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease. 2015

Nikpay, Majid / Goel, Anuj / Won, Hong-Hee / Hall, Leanne M / Willenborg, Christina / Kanoni, Stavroula / Saleheen, Danish / Kyriakou, Theodosios / Nelson, Christopher P / Hopewell, Jemma C / Webb, Thomas R / Zeng, Lingyao / Dehghan, Abbas / Alver, Maris / Armasu, Sebastian M / Auro, Kirsi / Bjonnes, Andrew / Chasman, Daniel I / Chen, Shufeng / Ford, Ian / Franceschini, Nora / Gieger, Christian / Grace, Christopher / Gustafsson, Stefan / Huang, Jie / Hwang, Shih-Jen / Kim, Yun Kyoung / Kleber, Marcus E / Lau, King Wai / Lu, Xiangfeng / Lu, Yingchang / Lyytikäinen, Leo-Pekka / Mihailov, Evelin / Morrison, Alanna C / Pervjakova, Natalia / Qu, Liming / Rose, Lynda M / Salfati, Elias / Saxena, Richa / Scholz, Markus / Smith, Albert V / Tikkanen, Emmi / Uitterlinden, Andre / Yang, Xueli / Zhang, Weihua / Zhao, Wei / de Andrade, Mariza / de Vries, Paul S / van Zuydam, Natalie R / Anand, Sonia S / Bertram, Lars / Beutner, Frank / Dedoussis, George / Frossard, Philippe / Gauguier, Dominique / Goodall, Alison H / Gottesman, Omri / Haber, Marc / Han, Bok-Ghee / Huang, Jianfeng / Jalilzadeh, Shapour / Kessler, Thorsten / König, Inke R / Lannfelt, Lars / Lieb, Wolfgang / Lind, Lars / Lindgren, Cecilia M / Lokki, Marja-Liisa / Magnusson, Patrik K / Mallick, Nadeem H / Mehra, Narinder / Meitinger, Thomas / Memon, Fazal-Ur-Rehman / Morris, Andrew P / Nieminen, Markku S / Pedersen, Nancy L / Peters, Annette / Rallidis, Loukianos S / Rasheed, Asif / Samuel, Maria / Shah, Svati H / Sinisalo, Juha / Stirrups, Kathleen E / Trompet, Stella / Wang, Laiyuan / Zaman, Khan S / Ardissino, Diego / Boerwinkle, Eric / Borecki, Ingrid B / Bottinger, Erwin P / Buring, Julie E / Chambers, John C / Collins, Rory / Cupples, L Adrienne / Danesh, John / Demuth, Ilja / Elosua, Roberto / Epstein, Stephen E / Esko, Tõnu / Feitosa, Mary F / Franco, Oscar H / Franzosi, Maria Grazia / Granger, Christopher B / Gu, Dongfeng / Gudnason, Vilmundur / Hall, Alistair S / Hamsten, Anders / Harris, Tamara B / Hazen, Stanley L / Hengstenberg, Christian / Hofman, Albert / Ingelsson, Erik / Iribarren, Carlos / Jukema, J Wouter / Karhunen, Pekka J / Kim, Bong-Jo / Kooner, Jaspal S / Kullo, Iftikhar J / Lehtimäki, Terho / Loos, Ruth J F / Melander, Olle / Metspalu, Andres / März, Winfried / Palmer, Colin N / Perola, Markus / Quertermous, Thomas / Rader, Daniel J / Ridker, Paul M / Ripatti, Samuli / Roberts, Robert / Salomaa, Veikko / Sanghera, Dharambir K / Schwartz, Stephen M / Seedorf, Udo / Stewart, Alexandre F / Stott, David J / Thiery, Joachim / Zalloua, Pierre A / O'Donnell, Christopher J / Reilly, Muredach P / Assimes, Themistocles L / Thompson, John R / Erdmann, Jeanette / Clarke, Robert / Watkins, Hugh / Kathiresan, Sekar / McPherson, Ruth / Deloukas, Panos / Schunkert, Heribert / Samani, Nilesh J / Farrall, Martin. ·Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Canada. · Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. · Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. · Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA. · Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. · Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. · Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. · Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. · Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Lübeck, Germany. · DZHK (German Research Center for Cardiovascular Research) partner site Hamburg-Lübeck-Kiel, Lübeck, Germany. · William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK. · Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Center for Non-Communicable Diseases, Karachi, Pakistan. · NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK. · CTSU, Nuffield Department of Population Health, University of Oxford, Oxford, UK. · Deutsches Herzzentrum München, Technische Universität München, München, Germany. · DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, München, Germany. · Department of Epidemiology, Erasmus University Medical center, Rotterdam, The Netherlands. · Estonian Genome Center, University of Tartu, Tartu, Estonia. · Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia. · Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA. · Department of Health, National Institute for Health and Welfare, Helsinki, Finland. · Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. · Diabetes & Obesity Research Program, University of Helsinki, Helsinki, Finland. · Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. · Harvard Medical School, Boston, Massachusetts, USA. · State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. · Robertson Center for Biostatistics, University of Glasgow, Glasgow, UK. · Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA. · Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. · Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. · Molecular Epidemiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden. · Science for Life Laboratory, Uppsala University, Uppsala, Sweden. · Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. · National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA. · Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA. · Center for Genome Science, Korea National Institute of Health, Chungcheongbuk-do, Korea. · Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany. · The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York, USA. · The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland. · Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland. · Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA. · Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, California, USA. · Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. · Institute for Medical Informatics, Statistics and Epidemiology, Medical Faculty, University of Leipzig, Leipzig, Germany. · LIFE Research Center of Civilization Diseases, Leipzig, Germany. · Icelandic Heart Association, Kopavogur, Iceland. · Faculty of Medicine, University of Iceland, Reykjavik, Iceland. · Department of Public Health, University of Helsinki, Helsinki, Finland. · Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland. · Department of Epidemiology and Biostatistics, Imperial College London, London, UK. · Department of Cardiology, Ealing Hospital NHS Trust, Middlesex, UK. · Medical Research Institute, University of Dundee, Dundee, UK. · Population Health Research Institute, Hamilton Health Sciences, Department of Medicine, McMaster University, Hamilton, Ontario, Canada. · Platform for Genome Analytics, Institutes of Neurogenetics & Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany. · Neuroepidemiology and Ageing Research Unit, School of Public Health, Faculty of Medicine, The Imperial College of Science, Technology, and Medicine, London, UK. · Heart Center Leipzig, Cardiology, University of Leipzig, Leipzig, Germany. · Department of Dietetics-Nutrition, Harokopio University, Athens, Greece. · INSERM, UMRS1138, Centre de Recherche des Cordeliers, Paris, France. · Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, UK. · Lebanese American University, School of Medicine, Beirut, Lebanon. · Hypertension Division, Fuwai Hospital, National Center For Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. · Klinikum rechts der Isar, München, Germany. · Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Lübeck, Germany. · Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden. · Institut für Epidemiologie, Christian-Albrechts Universität zu Kiel, Kiel, Germany. · Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden. · Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland. · Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. · Punjab Institute of Cardiology, Lahore, Pakistan. · All India Institute of Medical Sciences, New Delhi, India. · Institut für Humangenetik, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. · Institute of Human Genetics, Technische Universität München, München, Germany. · Red Crescent Institute of Cardiology, Hyderabad, Pakistan. · Department of Biostatistics, University of Liverpool, Liverpool, UK. · Department of Medicine, Department of Cardiology, Helsinki University Central Hospital, Helsinki, Finland. · Second Department of Cardiology, Attikon Hospital, School of Medicine, University of Athens, Athens, Greece. · Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA. · Department of Haematology, University of Cambridge, Cambridge, UK. · Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands. · Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands. · National Human Genome Center at Beijing, Beijing, China. · National Institue of Cardiovascular Diseases, Karachi, Pakistan. · Division of Cardiology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy. · Associazione per lo Studio della Trombosi in Cardiologia, Pavia, Italy. · Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA. · Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA. · Imperial College Healthcare NHS Trust, London, UK. · Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. · The Berlin Aging Study II; Research Group on Geriatrics; Charité - Universitätsmedizin Berlin, Berlin, Germany. · Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany. · Grupo de Epidemiología y Genética Cardiovascular, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain. · MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC, USA. · Division of Endocrinology and Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts, USA. · Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA. · Department of Cardiovascular Research, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy. · Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, UK. · Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden. · Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Cleveland Clinic, Cleveland, Ohio, USA. · Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA. · Kaiser Permanente Division of Research, Oakland, California, USA. · Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands. · Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands. · Department of Forensic Medicine, University of Tampere School of Medicine, Tampere, Finland. · Cardiovascular Science, National Heart and Lung Institute, Imperial College London, London, UK. · Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA. · The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Department of Clinical Sciences, Hypertension and Cardiovascular Disease, Lund University, University Hospital Malmö, Malmö, Sweden. · Synlab Academy, Synlab Services GmbH, Mannheim, Germany. · Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria. · Stanford Cardiovascular Institute, Stanford University, Stanford, California, USA. · Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA. · University of Ottawa Heart Institute, Ottawa, Canada. · Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland. · Department of Pediatrics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. · Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. · Oklahoma Center for Neuroscience, Oklahoma City, Oklahoma, USA. · Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. · Department of Epidemiology, University of Washington, Seattle, Washington, USA. · Department of Prosthetic Dentistry, Center for Dental and Oral Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow, UK. · Institute for Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Medical Faculty, Leipzig, Germany. · Harvard School of Public Health, Boston, Massachusetts, USA. · National Heart, Lung and Blood Institute Division of Intramural Research, Bethesda, Maryland, USA. · Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA. · Department of Health Sciences, University of Leicester, Leicester, UK. · Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia. ·Nat Genet · Pubmed #26343387.

ABSTRACT: Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.

15 Article Genetic variants primarily associated with type 2 diabetes are related to coronary artery disease risk. 2015

Jansen, Henning / Loley, Christina / Lieb, Wolfgang / Pencina, Michael J / Nelson, Christopher P / Kathiresan, Sekar / Peloso, Gina M / Voight, Benjamin F / Reilly, Muredach P / Assimes, Themistocles L / Boerwinkle, Eric / Hengstenberg, Christian / Laaksonen, Reijo / McPherson, Ruth / Roberts, Robert / Thorsteinsdottir, Unnur / Peters, Annette / Gieger, Christian / Rawal, Rajesh / Thompson, John R / König, Inke R / Anonymous2050833 / Vasan, Ramachandran S / Erdmann, Jeanette / Samani, Nilesh J / Schunkert, Heribert. ·Deutsches Herzzentrum and DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Technische Universität München, Munich, Germany. · Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Lübeck, Germany. · Institut für Epidemiologie, Universität zu Kiel, Kiel, Germany. · Department of Biostatistics and Bioinformatics, Duke Clinical Research Institute, Durham, NC, USA. · Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, LE3 9QP, UK; Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, LE3 9QP, UK. · Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, MA, USA; Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, MA, USA. · Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA. · The Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. · Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. · University of Texas Health Science Center, Human Genetics Center and Institute of Molecular Medicine, Houston, TX, USA. · Science Center, Tampere University Hospital, Tampere, Finland. · The John & Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Canada. · deCODE Genetics and University of Iceland, Faculty of Medicine, 101, Reykjavik, Iceland. · Institut für Epidemiologie II, Helmholtz Zentrum München, Neuherberg, Germany; Munich Heart Alliance, Munich, Germany. · Department of Health Sciences, University of Leicester, Leicester, UK. · School of Medicine, Section of Preventive Medicine and Epidemiology, Boston University, Boston, MA, USA. · Institut für Integrative und Experimentelle Genomik Universität zu Lübeck, DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Lübeck, Germany. ·Atherosclerosis · Pubmed #26074316.

ABSTRACT: BACKGROUND: The mechanisms underlying the association between diabetes and coronary artery disease (CAD) risk are unclear. We aimed to assess this association by studying genetic variants that have been shown to associate with type 2 diabetes (T2DM). If the association between diabetes and CAD is causal, we expected to observe an association of these variants with CAD as well. METHODS AND RESULTS: We studied all genetic variants currently known to be associated with T2DM at a genome-wide significant level (p < 5*10(-8)) in CARDIoGRAM, a genome-wide data-set of CAD including 22,233 CAD cases and 64,762 controls. Out of the 44 published T2DM SNPs 10 were significantly associated with CAD in CARDIoGRAM (OR>1, p < 0.05), more than expected by chance (p = 5.0*10(-5)). Considering all 44 SNPs, the average CAD risk observed per individual T2DM risk allele was 1.0076 (95% confidence interval (CI), 0.9973-1.0180). Such average risk increase was significantly lower than the increase expected based on i) the published effects of the SNPs on T2DM risk and ii) the effect of T2DM on CAD risk as observed in the Framingham Heart Study, which suggested a risk of 1.067 per allele (p = 7.2*10(-10) vs. the observed effect). Studying two risk scores based on risk alleles of the diabetes SNPs, one score using individual level data in 9856 subjects, and the second score on average effects of reported beta-coefficients from the entire CARDIoGRAM data-set, we again observed a significant - yet smaller than expected - association with CAD. CONCLUSIONS: Our data indicate that an association between type 2 diabetes related SNPs and CAD exists. However, the effects on CAD risk appear to be by far lower than what would be expected based on the effects of risk alleles on T2DM and the effect of T2DM on CAD in the epidemiological setting.

16 Article Characterization of TCF21 Downstream Target Regions Identifies a Transcriptional Network Linking Multiple Independent Coronary Artery Disease Loci. 2015

Sazonova, Olga / Zhao, Yuqi / Nürnberg, Sylvia / Miller, Clint / Pjanic, Milos / Castano, Victor G / Kim, Juyong B / Salfati, Elias L / Kundaje, Anshul B / Bejerano, Gill / Assimes, Themistocles / Yang, Xia / Quertermous, Thomas. ·Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, United States of America; Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, United States of America. · Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, California, United States of America. · Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, United States of America. · Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America. · Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, United States of America; Department of Computer Science, Stanford University School of Medicine, Stanford, California, United States of America; Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America; Department of Developmental Biology, Stanford University School of Medicine, Stanford, California, United States of America. ·PLoS Genet · Pubmed #26020271.

ABSTRACT: To functionally link coronary artery disease (CAD) causal genes identified by genome wide association studies (GWAS), and to investigate the cellular and molecular mechanisms of atherosclerosis, we have used chromatin immunoprecipitation sequencing (ChIP-Seq) with the CAD associated transcription factor TCF21 in human coronary artery smooth muscle cells (HCASMC). Analysis of identified TCF21 target genes for enrichment of molecular and cellular annotation terms identified processes relevant to CAD pathophysiology, including "growth factor binding," "matrix interaction," and "smooth muscle contraction." We characterized the canonical binding sequence for TCF21 as CAGCTG, identified AP-1 binding sites in TCF21 peaks, and by conducting ChIP-Seq for JUN and JUND in HCASMC confirmed that there is significant overlap between TCF21 and AP-1 binding loci in this cell type. Expression quantitative trait variation mapped to target genes of TCF21 was significantly enriched among variants with low P-values in the GWAS analyses, suggesting a possible functional interaction between TCF21 binding and causal variants in other CAD disease loci. Separate enrichment analyses found over-representation of TCF21 target genes among CAD associated genes, and linkage disequilibrium between TCF21 peak variation and that found in GWAS loci, consistent with the hypothesis that TCF21 may affect disease risk through interaction with other disease associated loci. Interestingly, enrichment for TCF21 target genes was also found among other genome wide association phenotypes, including height and inflammatory bowel disease, suggesting a functional profile important for basic cellular processes in non-vascular tissues. Thus, data and analyses presented here suggest that study of GWAS transcription factors may be a highly useful approach to identifying disease gene interactions and thus pathways that may be relevant to complex disease etiology.

17 Article Systems Genetics Analysis of Genome-Wide Association Study Reveals Novel Associations Between Key Biological Processes and Coronary Artery Disease. 2015

Ghosh, Sujoy / Vivar, Juan / Nelson, Christopher P / Willenborg, Christina / Segrè, Ayellet V / Mäkinen, Ville-Petteri / Nikpay, Majid / Erdmann, Jeannette / Blankenberg, Stefan / O'Donnell, Christopher / März, Winfried / Laaksonen, Reijo / Stewart, Alexandre F R / Epstein, Stephen E / Shah, Svati H / Granger, Christopher B / Hazen, Stanley L / Kathiresan, Sekar / Reilly, Muredach P / Yang, Xia / Quertermous, Thomas / Samani, Nilesh J / Schunkert, Heribert / Assimes, Themistocles L / McPherson, Ruth. · ·Arterioscler Thromb Vasc Biol · Pubmed #25977570.

ABSTRACT: OBJECTIVE: Genome-wide association studies have identified multiple genetic variants affecting the risk of coronary artery disease (CAD). However, individually these explain only a small fraction of the heritability of CAD and for most, the causal biological mechanisms remain unclear. We sought to obtain further insights into potential causal processes of CAD by integrating large-scale GWA data with expertly curated databases of core human pathways and functional networks. APPROACHES AND RESULTS: Using pathways (gene sets) from Reactome, we carried out a 2-stage gene set enrichment analysis strategy. From a meta-analyzed discovery cohort of 7 CAD genome-wide association study data sets (9889 cases/11 089 controls), nominally significant gene sets were tested for replication in a meta-analysis of 9 additional studies (15 502 cases/55 730 controls) from the Coronary ARtery DIsease Genome wide Replication and Meta-analysis (CARDIoGRAM) Consortium. A total of 32 of 639 Reactome pathways tested showed convincing association with CAD (replication P<0.05). These pathways resided in 9 of 21 core biological processes represented in Reactome, and included pathways relevant to extracellular matrix (ECM) integrity, innate immunity, axon guidance, and signaling by PDRF (platelet-derived growth factor), NOTCH, and the transforming growth factor-β/SMAD receptor complex. Many of these pathways had strengths of association comparable to those observed in lipid transport pathways. Network analysis of unique genes within the replicated pathways further revealed several interconnected functional and topologically interacting modules representing novel associations (eg, semaphoring-regulated axonal guidance pathway) besides confirming known processes (lipid metabolism). The connectivity in the observed networks was statistically significant compared with random networks (P<0.001). Network centrality analysis (degree and betweenness) further identified genes (eg, NCAM1, FYN, FURIN, etc) likely to play critical roles in the maintenance and functioning of several of the replicated pathways. CONCLUSIONS: These findings provide novel insights into how genetic variation, interpreted in the context of biological processes and functional interactions among genes, may help define the genetic architecture of CAD.

18 Article Genetically determined height and coronary artery disease. 2015

Nelson, Christopher P / Hamby, Stephen E / Saleheen, Danish / Hopewell, Jenna C / Zeng, Lingyao / Assimes, Themistocles L / Kanoni, Stavroula / Willenborg, Christina / Burgess, Stephen / Amouyel, Phillipe / Anand, Sonia / Blankenberg, Stefan / Boehm, Bernhard O / Clarke, Robert J / Collins, Rory / Dedoussis, George / Farrall, Martin / Franks, Paul W / Groop, Leif / Hall, Alistair S / Hamsten, Anders / Hengstenberg, Christian / Hovingh, G Kees / Ingelsson, Erik / Kathiresan, Sekar / Kee, Frank / König, Inke R / Kooner, Jaspal / Lehtimäki, Terho / März, Winifred / McPherson, Ruth / Metspalu, Andres / Nieminen, Markku S / O'Donnell, Christopher J / Palmer, Colin N A / Peters, Annette / Perola, Markus / Reilly, Muredach P / Ripatti, Samuli / Roberts, Robert / Salomaa, Veikko / Shah, Svati H / Schreiber, Stefan / Siegbahn, Agneta / Thorsteinsdottir, Unnur / Veronesi, Giovani / Wareham, Nicholas / Willer, Cristen J / Zalloua, Pierre A / Erdmann, Jeanette / Deloukas, Panos / Watkins, Hugh / Schunkert, Heribert / Danesh, John / Thompson, John R / Samani, Nilesh J / Anonymous2660826. ·The authors' affiliations are listed in the Appendix. ·N Engl J Med · Pubmed #25853659.

ABSTRACT: BACKGROUND: The nature and underlying mechanisms of an inverse association between adult height and the risk of coronary artery disease (CAD) are unclear. METHODS: We used a genetic approach to investigate the association between height and CAD, using 180 height-associated genetic variants. We tested the association between a change in genetically determined height of 1 SD (6.5 cm) with the risk of CAD in 65,066 cases and 128,383 controls. Using individual-level genotype data from 18,249 persons, we also examined the risk of CAD associated with the presence of various numbers of height-associated alleles. To identify putative mechanisms, we analyzed whether genetically determined height was associated with known cardiovascular risk factors and performed a pathway analysis of the height-associated genes. RESULTS: We observed a relative increase of 13.5% (95% confidence interval [CI], 5.4 to 22.1; P<0.001) in the risk of CAD per 1-SD decrease in genetically determined height. There was a graded relationship between the presence of an increased number of height-raising variants and a reduced risk of CAD (odds ratio for height quartile 4 versus quartile 1, 0.74; 95% CI, 0.68 to 0.84; P<0.001). Of the 12 risk factors that we studied, we observed significant associations only with levels of low-density lipoprotein cholesterol and triglycerides (accounting for approximately 30% of the association). We identified several overlapping pathways involving genes associated with both development and atherosclerosis. CONCLUSIONS: There is a primary association between a genetically determined shorter height and an increased risk of CAD, a link that is partly explained by the association between shorter height and an adverse lipid profile. Shared biologic processes that determine achieved height and the development of atherosclerosis may explain some of the association. (Funded by the British Heart Foundation and others.).

19 Article Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. 2015

Do, Ron / Stitziel, Nathan O / Won, Hong-Hee / Jørgensen, Anders Berg / Duga, Stefano / Angelica Merlini, Pier / Kiezun, Adam / Farrall, Martin / Goel, Anuj / Zuk, Or / Guella, Illaria / Asselta, Rosanna / Lange, Leslie A / Peloso, Gina M / Auer, Paul L / Anonymous4660814 / Girelli, Domenico / Martinelli, Nicola / Farlow, Deborah N / DePristo, Mark A / Roberts, Robert / Stewart, Alexander F R / Saleheen, Danish / Danesh, John / Epstein, Stephen E / Sivapalaratnam, Suthesh / Hovingh, G Kees / Kastelein, John J / Samani, Nilesh J / Schunkert, Heribert / Erdmann, Jeanette / Shah, Svati H / Kraus, William E / Davies, Robert / Nikpay, Majid / Johansen, Christopher T / Wang, Jian / Hegele, Robert A / Hechter, Eliana / Marz, Winfried / Kleber, Marcus E / Huang, Jie / Johnson, Andrew D / Li, Mingyao / Burke, Greg L / Gross, Myron / Liu, Yongmei / Assimes, Themistocles L / Heiss, Gerardo / Lange, Ethan M / Folsom, Aaron R / Taylor, Herman A / Olivieri, Oliviero / Hamsten, Anders / Clarke, Robert / Reilly, Dermot F / Yin, Wu / Rivas, Manuel A / Donnelly, Peter / Rossouw, Jacques E / Psaty, Bruce M / Herrington, David M / Wilson, James G / Rich, Stephen S / Bamshad, Michael J / Tracy, Russell P / Cupples, L Adrienne / Rader, Daniel J / Reilly, Muredach P / Spertus, John A / Cresci, Sharon / Hartiala, Jaana / Tang, W H Wilson / Hazen, Stanley L / Allayee, Hooman / Reiner, Alex P / Carlson, Christopher S / Kooperberg, Charles / Jackson, Rebecca D / Boerwinkle, Eric / Lander, Eric S / Schwartz, Stephen M / Siscovick, David S / McPherson, Ruth / Tybjaerg-Hansen, Anne / Abecasis, Goncalo R / Watkins, Hugh / Nickerson, Deborah A / Ardissino, Diego / Sunyaev, Shamil R / O'Donnell, Christopher J / Altshuler, David / Gabriel, Stacey / Kathiresan, Sekar. ·1] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. [2] Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. [3] Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA. [4] Program in Medical and Population Genetics, Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA. · 1] Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA. [2] Division of Statistical Genomics, Washington University School of Medicine, St Louis, Missouri 63110, USA. · Department of Clinical Biochemistry KB3011, Section for Molecular Genetics, Rigshospitalet, Copenhagen University Hospitals and Faculty of Health Sciences, University of Copenhagen, Copenhagen 1165, Denmark. · Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milano 20122, Italy. · Division of Cardiology, Ospedale Niguarda, Milano 20162, Italy. · Program in Medical and Population Genetics, Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA. · Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX1 2J, UK. · Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA. · Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. · University of Verona School of Medicine, Department of Medicine, Verona 37129, Italy. · John &Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Ontario K1Y 4W7, Canada. · Department of Public Health and Primary Care, University of Cambridge, Cambridge CB2 1TN, UK. · MedStar Health Research Institute, Cardiovascular Research Institute, Hyattsville, Maryland 20782, USA. · Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands. · Department of Cardiovascular Sciences, University of Leicester, and Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester LE3 9QP, UK. · DZHK (German Research Centre for Cardiovascular Research), Munich Heart Alliance, Deutsches Herzzentrum München, Technische Universität München, Berlin 13347, Germany. · Medizinische Klinik II, University of Lübeck, Lübeck 23562, Germany. · 1] Center for Human Genetics, Duke University, Durham, North Carolina 27708, USA. [2] Department of Cardiology and Center for Genomic Medicine, Duke University School of Medicine, Durham, North Carolina 27708, USA. · Department of Cardiology and Center for Genomic Medicine, Duke University School of Medicine, Durham, North Carolina 27708, USA. · Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario K1Y 4W7, Canada. · Department of Biochemistry, Schulich School of Medicine and Dentistry, Robarts Research Institute, University of Western Ontario, London, Ontario N6A 3K7, Canada. · 1] Department of Biochemistry, Schulich School of Medicine and Dentistry, Robarts Research Institute, University of Western Ontario, London, Ontario N6A 3K7, Canada. [2] Department of Medicine, Schulich School of Medicine and Dentistry, Robarts Research Institute, University of Western Ontario, London, Ontario N6A 3K7, Canada. · 1] Medical Faculty Mannheim, Mannheim Institute of Public Health, Social and Preventive Medicine, Heidelberg University, Ludolf Krehl Strasse 7-11, Mannheim D-68167, Germany. [2] Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz 8036, Austria. [3] Synlab Academy, Mannheim 68259, Germany. · Medical Faculty Mannheim, Mannheim Institute of Public Health, Social and Preventive Medicine, Heidelberg University, Ludolf Krehl Strasse 7-11, Mannheim D-68167, Germany. · The National Heart, Lung, Blood Institute's Framingham Heart Study, Framingham, Massachusetts 01702, USA. · National Heart, Lung, and Blood Institute Center for Population Studies, The Framingham Heart Study, Framingham, Massachusetts 01702, USA. · Department of Biostatistics and Epidemiology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. · Department of Epidemiology, University of Alabama-Birmingham, Birmingham, Alabama 35233, USA. · Department of Laboratory Medicine and Pathology, School of Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA. · School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27106, USA. · Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA. · Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina 27599, USA. · 1] Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA. [2] Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, North Carolina 27599, USA. · Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, Minnesota 55455, USA. · University of Mississippi Medical Center, Jackson, Mississippi 39216, USA. · Atherosclerosis Research Unit, Department of Medicine, and Center for Molecular Medicine, Karolinska Institutet, Stockholm 171 77, Sweden. · Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Oxford OX1 2JD, UK. · Merck Sharp &Dohme Corporation, Rahway, New Jersey 08889, USA. · The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX1 2JD, UK. · 1] The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX1 2JD, UK. [2] Department of Statistics, University of Oxford, Oxford OX1 2JD, UK. · National Heart, Lung, and Blood Institute, Bethesda, Maryland 20824, USA. · 1] Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, Washington 98195, USA. [2] Group Health Research Institute, Group Health Cooperative, Seattle, Washington 98101, USA. · Section on Cardiology, and Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina 27106, USA. · Jackson Heart Study, University of Mississippi Medical Center, Jackson State University, Jackson, Mississippi 39217, USA. · Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22904, USA. · 1] Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA. [2] Seattle Children's Hospital, Seattle, Washington 98105, USA. [3] Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA. · Department of Biochemistry, University of Vermont, Burlington, Vermont 05405, USA. · Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA. · Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. · Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. · St Luke's Mid America Heart Institute, University of Missouri-Kansas City, Kansas City, Missouri 64111, USA. · 1] Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA. [2] Department of Genetics, Washington University in St Louis, Missouri 63130, USA. · Department of Preventive Medicine and Institute for Genetic Medicine, University of Southern California Keck School of Medicine, Los Angeles, California 90033, USA. · Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio 44195, USA. · 1] Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. [2] Department of Epidemiology, University of Washington, Seattle, Washington 98195, USA. · Ohio State University, Columbus, Ohio 43210, USA. · Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA. · 1] Department of Epidemiology, University of Washington, Seattle, Washington 98195, USA. [2] Department of Medicine, School of Medicine, University of Washington, Seattle, Washington 98195, USA. · 1] Department of Clinical Biochemistry KB3011, Section for Molecular Genetics, Rigshospitalet, Copenhagen University Hospitals and Faculty of Health Sciences, University of Copenhagen, Copenhagen 1165, Denmark. [2] Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 København N, Denmark. · Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Missouri 48109, USA. · 1] Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX1 2J, UK. [2] The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX1 2JD, UK. · Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA. · Department of Cardiology, Parma Hospital, Parma 43100, Italy. · 1] Program in Medical and Population Genetics, Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA. [2] Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. · 1] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. [2] Program in Medical and Population Genetics, Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA. ·Nature · Pubmed #25487149.

ABSTRACT: Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.

20 Article Integrative genomics reveals novel molecular pathways and gene networks for coronary artery disease. 2014

Mäkinen, Ville-Petteri / Civelek, Mete / Meng, Qingying / Zhang, Bin / Zhu, Jun / Levian, Candace / Huan, Tianxiao / Segrè, Ayellet V / Ghosh, Sujoy / Vivar, Juan / Nikpay, Majid / Stewart, Alexandre F R / Nelson, Christopher P / Willenborg, Christina / Erdmann, Jeanette / Blakenberg, Stefan / O'Donnell, Christopher J / März, Winfried / Laaksonen, Reijo / Epstein, Stephen E / Kathiresan, Sekar / Shah, Svati H / Hazen, Stanley L / Reilly, Muredach P / Anonymous5400800 / Lusis, Aldons J / Samani, Nilesh J / Schunkert, Heribert / Quertermous, Thomas / McPherson, Ruth / Yang, Xia / Assimes, Themistocles L. ·Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, California, United States of America; South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia; School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia. · Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America. · Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, California, United States of America. · Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America. · National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America. · Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America. · Department of Cardiovascular and Metabolic Research, Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina, United States of America; Program in Cardiovascular and Metabolic Disorders and Centre for Computational Biology, Duke-NUS Graduate Medical School, Singapore. · Department of Cardiovascular and Metabolic Research, Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina, United States of America. · Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada. · John and Jennifer Ruddy Canadian Cardiovascular Research Center, University of Ottawa Heart Institute, Ottawa, Ontario, Canada. · Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, United Kingdom; National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom. · Institut für Integrative und Experimentelle Genomik, University of Lübeck, Lübeck, Germany. · Institut für Integrative und Experimentelle Genomik, University of Lübeck, Lübeck, Germany; DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg, Kiel, Lübeck, Germany. · Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany. · National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America; Cardiology Division, Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America. · Mannheim Institute of Public Health, Social and Preventive Medicine, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany; Synlab Academy, Mannheim, Germany. · Science Center, Tampere University Hospital, Tampere, Finland. · Cardiovascular Research Institute, Washington Hospital Center, Washington, D.C., United States of America. · National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America; Cardiology Division, Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America; Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America. · Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America. · Cleveland Clinic, Cleveland, Ohio, United States of America. · Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America. · DZHK (German Research Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany; Deutsches Herzzentrum München, Technische Universität München, Munich, Germany. · Department of Medicine, Stanford University School of Medicine, Stanford, California, United States of America. ·PLoS Genet · Pubmed #25033284.

ABSTRACT: The majority of the heritability of coronary artery disease (CAD) remains unexplained, despite recent successes of genome-wide association studies (GWAS) in identifying novel susceptibility loci. Integrating functional genomic data from a variety of sources with a large-scale meta-analysis of CAD GWAS may facilitate the identification of novel biological processes and genes involved in CAD, as well as clarify the causal relationships of established processes. Towards this end, we integrated 14 GWAS from the CARDIoGRAM Consortium and two additional GWAS from the Ottawa Heart Institute (25,491 cases and 66,819 controls) with 1) genetics of gene expression studies of CAD-relevant tissues in humans, 2) metabolic and signaling pathways from public databases, and 3) data-driven, tissue-specific gene networks from a multitude of human and mouse experiments. We not only detected CAD-associated gene networks of lipid metabolism, coagulation, immunity, and additional networks with no clear functional annotation, but also revealed key driver genes for each CAD network based on the topology of the gene regulatory networks. In particular, we found a gene network involved in antigen processing to be strongly associated with CAD. The key driver genes of this network included glyoxalase I (GLO1) and peptidylprolyl isomerase I (PPIL1), which we verified as regulatory by siRNA experiments in human aortic endothelial cells. Our results suggest genetic influences on a diverse set of both known and novel biological processes that contribute to CAD risk. The key driver genes for these networks highlight potential novel targets for further mechanistic studies and therapeutic interventions.

21 Article Discovery and refinement of loci associated with lipid levels. 2013

Willer, Cristen J / Schmidt, Ellen M / Sengupta, Sebanti / Peloso, Gina M / Gustafsson, Stefan / Kanoni, Stavroula / Ganna, Andrea / Chen, Jin / Buchkovich, Martin L / Mora, Samia / Beckmann, Jacques S / Bragg-Gresham, Jennifer L / Chang, Hsing-Yi / Demirkan, Ayşe / Den Hertog, Heleen M / Do, Ron / Donnelly, Louise A / Ehret, Georg B / Esko, Tõnu / Feitosa, Mary F / Ferreira, Teresa / Fischer, Krista / Fontanillas, Pierre / Fraser, Ross M / Freitag, Daniel F / Gurdasani, Deepti / Heikkilä, Kauko / Hyppönen, Elina / Isaacs, Aaron / Jackson, Anne U / Johansson, Åsa / Johnson, Toby / Kaakinen, Marika / Kettunen, Johannes / Kleber, Marcus E / Li, Xiaohui / Luan, Jian'an / Lyytikäinen, Leo-Pekka / Magnusson, Patrik K E / Mangino, Massimo / Mihailov, Evelin / Montasser, May E / Müller-Nurasyid, Martina / Nolte, Ilja M / O'Connell, Jeffrey R / Palmer, Cameron D / Perola, Markus / Petersen, Ann-Kristin / Sanna, Serena / Saxena, Richa / Service, Susan K / Shah, Sonia / Shungin, Dmitry / Sidore, Carlo / Song, Ci / Strawbridge, Rona J / Surakka, Ida / Tanaka, Toshiko / Teslovich, Tanya M / Thorleifsson, Gudmar / Van den Herik, Evita G / Voight, Benjamin F / Volcik, Kelly A / Waite, Lindsay L / Wong, Andrew / Wu, Ying / Zhang, Weihua / Absher, Devin / Asiki, Gershim / Barroso, Inês / Been, Latonya F / Bolton, Jennifer L / Bonnycastle, Lori L / Brambilla, Paolo / Burnett, Mary S / Cesana, Giancarlo / Dimitriou, Maria / Doney, Alex S F / Döring, Angela / Elliott, Paul / Epstein, Stephen E / Ingi Eyjolfsson, Gudmundur / Gigante, Bruna / Goodarzi, Mark O / Grallert, Harald / Gravito, Martha L / Groves, Christopher J / Hallmans, Göran / Hartikainen, Anna-Liisa / Hayward, Caroline / Hernandez, Dena / Hicks, Andrew A / Holm, Hilma / Hung, Yi-Jen / Illig, Thomas / Jones, Michelle R / Kaleebu, Pontiano / Kastelein, John J P / Khaw, Kay-Tee / Kim, Eric / Klopp, Norman / Komulainen, Pirjo / Kumari, Meena / Langenberg, Claudia / Lehtimäki, Terho / Lin, Shih-Yi / Lindström, Jaana / Loos, Ruth J F / Mach, François / McArdle, Wendy L / Meisinger, Christa / Mitchell, Braxton D / Müller, Gabrielle / Nagaraja, Ramaiah / Narisu, Narisu / Nieminen, Tuomo V M / Nsubuga, Rebecca N / Olafsson, Isleifur / Ong, Ken K / Palotie, Aarno / Papamarkou, Theodore / Pomilla, Cristina / Pouta, Anneli / Rader, Daniel J / Reilly, Muredach P / Ridker, Paul M / Rivadeneira, Fernando / Rudan, Igor / Ruokonen, Aimo / Samani, Nilesh / Scharnagl, Hubert / Seeley, Janet / Silander, Kaisa / Stančáková, Alena / Stirrups, Kathleen / Swift, Amy J / Tiret, Laurence / Uitterlinden, Andre G / van Pelt, L Joost / Vedantam, Sailaja / Wainwright, Nicholas / Wijmenga, Cisca / Wild, Sarah H / Willemsen, Gonneke / Wilsgaard, Tom / Wilson, James F / Young, Elizabeth H / Zhao, Jing Hua / Adair, Linda S / Arveiler, Dominique / Assimes, Themistocles L / Bandinelli, Stefania / Bennett, Franklyn / Bochud, Murielle / Boehm, Bernhard O / Boomsma, Dorret I / Borecki, Ingrid B / Bornstein, Stefan R / Bovet, Pascal / Burnier, Michel / Campbell, Harry / Chakravarti, Aravinda / Chambers, John C / Chen, Yii-Der Ida / Collins, Francis S / Cooper, Richard S / Danesh, John / Dedoussis, George / de Faire, Ulf / Feranil, Alan B / Ferrières, Jean / Ferrucci, Luigi / Freimer, Nelson B / Gieger, Christian / Groop, Leif C / Gudnason, Vilmundur / Gyllensten, Ulf / Hamsten, Anders / Harris, Tamara B / Hingorani, Aroon / Hirschhorn, Joel N / Hofman, Albert / Hovingh, G Kees / Hsiung, Chao Agnes / Humphries, Steve E / Hunt, Steven C / Hveem, Kristian / Iribarren, Carlos / Järvelin, Marjo-Riitta / Jula, Antti / Kähönen, Mika / Kaprio, Jaakko / Kesäniemi, Antero / Kivimaki, Mika / Kooner, Jaspal S / Koudstaal, Peter J / Krauss, Ronald M / Kuh, Diana / Kuusisto, Johanna / Kyvik, Kirsten O / Laakso, Markku / Lakka, Timo A / Lind, Lars / Lindgren, Cecilia M / Martin, Nicholas G / März, Winfried / McCarthy, Mark I / McKenzie, Colin A / Meneton, Pierre / Metspalu, Andres / Moilanen, Leena / Morris, Andrew D / Munroe, Patricia B / Njølstad, Inger / Pedersen, Nancy L / Power, Chris / Pramstaller, Peter P / Price, Jackie F / Psaty, Bruce M / Quertermous, Thomas / Rauramaa, Rainer / Saleheen, Danish / Salomaa, Veikko / Sanghera, Dharambir K / Saramies, Jouko / Schwarz, Peter E H / Sheu, Wayne H-H / Shuldiner, Alan R / Siegbahn, Agneta / Spector, Tim D / Stefansson, Kari / Strachan, David P / Tayo, Bamidele O / Tremoli, Elena / Tuomilehto, Jaakko / Uusitupa, Matti / van Duijn, Cornelia M / Vollenweider, Peter / Wallentin, Lars / Wareham, Nicholas J / Whitfield, John B / Wolffenbuttel, Bruce H R / Ordovas, Jose M / Boerwinkle, Eric / Palmer, Colin N A / Thorsteinsdottir, Unnur / Chasman, Daniel I / Rotter, Jerome I / Franks, Paul W / Ripatti, Samuli / Cupples, L Adrienne / Sandhu, Manjinder S / Rich, Stephen S / Boehnke, Michael / Deloukas, Panos / Kathiresan, Sekar / Mohlke, Karen L / Ingelsson, Erik / Abecasis, Gonçalo R / Anonymous3140771. ·Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA. · Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA. · Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA. · Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA. · Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA. · Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. · Broad Institute, Program in Medical and Population Genetics, Cambridge, Massachusetts 02142, USA. · Department of Medical Sciences, Molecular Epidemiology, Uppsala University, Uppsala, Sweden. · Science for Life Laboratory, Uppsala University, Uppsala, Sweden. · Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, CB10 1SA, Hinxton, United Kingdom. · Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. · Department of Genetics, University of North Carolina, Chapel Hill, NC 27599 USA. · Division of Preventive Medicine, Brigham and Women's Hospital, 900 Commonwealth Ave., Boston MA 02215, USA. · Harvard Medical School, Boston MA 02115, USA. · Service of Medical Genetics, Lausanne University Hospital, Lausanne, Switzerland. · Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland. · Division of Preventive Medicine and Health Services Research, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan. · Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands. · Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands. · Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School. Dundee, DD1 9SY, United Kingdom. · Cardiology, Department of Specialities of Medicine, Geneva University Hospital, Rue Gabrielle-Perret-Gentil 4, 1211 Geneva 14, Switzerland. · Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Estonian Genome Center of the University of Tartu, Tartu, Estonia. · Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia. · Department of Genetics, Washington University School of Medicine, USA. · Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, United Kingdom. · Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, Scotland, United Kingdom. · Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. · Hjelt Institute, Department of Public Health, University of Helsinki, Finland. · Centre For Paediatric Epidemiology and Biostatistics/MRC Centre of Epidemiology for Child Health, University College of London Institute of Child Health, London, United Kingdom. · Centre for Medical Systems Biology, Leiden, the Netherlands. · Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. · Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden. · Genome Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. · Clinical Pharmacology, NIHR Cardiovascular Biomedical Research Unit, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry Queen Mary University of London, London, UK. · Biocenter Oulu, University of Oulu, Oulu, Finland. · Institute of Health Sciences, University of Oulu, Finland. · Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland. · Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland. · Department of Internal Medicine II - Cardiology, University of Ulm Medical Centre, Ulm, Germany. · Mannheim Institute of Public Health, Social and Preventive Medicine, Medical Faculty of Mannheim, University of Heidelberg, Ludolf-Krehl-Strasse 7-11, 68167 Mannheim, Germany. · Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. · MRC Epidemiology Unit, Institute of Metabolic Science, Box 285, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, United Kingdom. · Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33520, Finland. · Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere 33014, Finland. · Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom. · Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland, School of Medicine, Baltimore, Maryland. · Institute of Genetic Epidemiology, Helmholtz Zentrum München, Neuherberg 85764, Germany. · Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians University, Munich, Germany. · Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-University of Munich, Munich, Germany. · Department of Epidemiology, University of Groningen, University Medical Center Groningen, The Netherlands. · Division of Endocrinology, Children's Hospital Boston, Massachusetts 02115, USA. · Division of Genetics, Program in Genomics, Children's Hospital, Boston, Massachusetts 02115, USA. · Istituto di Ricerca Genetica e Biomedica, CNR, Monserrato, 09042, Italy. · Massachusetts General Hospital/Broad Institute, Harvard University, Cambridge, MA, USA. · Center for Neurobehavioral Genetics, The Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, USA. · Genetic Epidemiology Group, Deparment of Epidemiology and Public Health, UCL, London WC1E 6BT, United Kingdom. · Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit, Lund University Diabetes Center, Scania University Hosptial, Malmö, Sweden. · Department of Odontology, Umeå University, Umeå, Sweden. · Department of Public Health and Primary Care, Unit of Medicine, Umeå University, Umeå, Sweden. · Dipartimento di Scienze Biomediche, Universita di Sassari, 07100 SS, Italy. · Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden. · Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden. · Clinical Research Branch, National Institute Health, Baltimore, MD, USA. · deCODE Genetics/Amgen, 101 Reykjavik, Iceland. · Department of Genetics, University of Pennsylvania - School of Medicine, Philadelphia PA, 19104, USA. · Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania - School of Medicine, Philadelphia PA, 19104, USA. · Human Genetics Center, University of Texas Health Science Center - School of Public Health, Houston, TX 77030, USA. · HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA. · MRC Unit for Lifelong Health and Ageing, 33 Bedford Place, London, WC1B 5JU, United Kingdom. · Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom. · Ealing Hospital, Southall, Middlesex UB1 3HW, United Kingdom. · MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda. · University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Level 4, Institute of Metabolic Science Box 289 Addenbrooke's Hospital Cambridge CB2 OQQ, UK. · Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. · Genome Technology Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA. · Department of Experimental Medicine, University of Milano Bicocca, Italy. · MedStar Health Research Institute, 6525 Belcrest Road, Suite 700, Hyattsville, MD 20782, USA. · Research Centre on Public Health, University of Milano Bicocca, Italy. · Department of Dietetics-Nutrition, Harokopio University, 70 El. Venizelou Str, Athens, Greece. · Institute of Epidemiology I, Helmholtz Zentrum München, Neuherberg 85764, Germany. · Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg 85764, Germany. · Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA) Centre for Environment and Health, School of Public Health, Imperial College London, UK. · The Laboratory in Mjodd, 108 Reykjavik, Iceland. · Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. · Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. · Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg 85764, Germany. · Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, OX3 7LJ, United Kingdom. · Department of Public Health and Clinical Medicine, Nutritional research, Umeå University, Umeå, Sweden. · Department of Clinical Sciences/Obstetrics and Gynecology, Oulu University Hospital, Oulu, Finland. · MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland, United Kingdom. · Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA. · Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy - Affiliated Institute of the University of Lübeck, Lübeck, Germany. · Division of Endocrinology & Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. · Hannover Unified Biobank, Hannover Medical School, Hannover 30625, Germany. · Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. · Clinical Gerontology Unit, University of Cambridge, Cambridge, United Kingdom. · Kuopio Research Institute of Exercise Medicine, Kuopio, Finland. · Division of Endocrine and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, School of Medicine, National Yang-Ming University, Taipei, Taiwan. · Diabetes Prevention Unit, National Institute for Health and Welfare, 00271 Helsinki, Finland. · The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, USA. · The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at ount Sinai, New York, USA. · The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York. · School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, United Kingdom. · Institute for Medical Informatics and Biometrics, University of Dresden, Medical Faculty Carl Gustav Carus, Fetscherstrasse 74, 01307 Dresden, Germany. · Laboratory of Genetics, National Institute on Aging, Baltimore, MD21224, USA. · Department of Clinical Pharmacology, University of Tampere School of Medicine, Tamperew 33014, Finland. · Department of Internal Medicine, Päijät-Häme Central Hospital, Lahti, Finland. · Division of Cardiology, Helsinki University Central Hospital, Helsinki, Finland. · Department of Clinical Biochemistry, Landspitali University Hospital, 101 Reykjavik, Iceland. · Department of Medical Genetics, Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. · Genetic Epidemiology Group, Wellcome Trust Sanger Institute, Hinxton, Cambridge, United ingdom. · Department of Statistical Sciences, University College of London, London, United Kingdom. · National Institute for Health and Welfare, Oulu, Finland. · Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Blvd, Building 421, Translational Research Center, Philadelphia, PA 19104-5158, USA. · Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Blvd, Building 421, Translational Research Center, Philadelphia, PA 19104-5158, USA. · Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands. · Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands. · Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging NCHA), Leiden, The Netherlands. · Department of Clinical Sciences/Clinical Chemistry, University of Oulu, Oulu, Finland. · National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, UK. · Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, LE3 9QP, UK. · Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Austria. · School of International Development, University of East Anglia, Norwich NR4 7TJ, United Kingdom. · University of Eastern Finland and Kuopio University Hospital, 70210 Kuopio, Finland. · INSERM UMRS 937, Pierre and Marie Curie University, Paris, France. · Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, The Netherlands. · LifeLines Cohort Study, University of Groningen, University Medical Center Groningen, The Netherlands. · Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands. · Department of Biological Psychology, VU Univ, Amsterdam, The Netherlands. · Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway. · Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA. · Department of Epidemiology and Public Health, EA 3430, University of Strasbourg, Faculty of Medicine, Strasbourg, France. · Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. · Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy. · Chemical Pathology, Department of Pathology, University of the West Indies, Mona, Kingston 7, Jamaica. · Institute of Social and Preventive Medicine (IUMSP), Lausanne University Hospital, Route de la Corniche 10, 1010 Lausanne, Switzerland. · Division of Endocrinology and Diabetes, Department of Internal Medicine, Ulm University Medical Centre, Ulm, Germany. · Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore. · Department of Medicine III, University of Dresden, Medical Faculty Carl Gustav Carus, Fetscherstrasse 74, 01307 Dresden, Germany. · Ministry of Health, Victoria, Republic of Seychelles. · Service of Nephrology, Lausanne University Hospital, Lausanne, Switzerland. · Imperial College Healthcare NHS Trust, London, United Kingdom. · Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, California, USA. · Department of Medicine, University of California Los Angeles, Los Angeles, California, USA. · Department of Preventive Medicine and Epidemiology, Loyola University Medical School, Maywood, Illinois 60153, USA. · Office of Population Studies Foundation, University of San Carlos, Talamban, Cebu City, Philippines. · Department of Cardiology, Toulouse University School of Medicine, Rangueil Hospital, Toulouse, France. · Department of Psychiatry, University of California, Los Angeles, USA. · Department of Clinical Sciences, Lund University, SE-20502, Malmö, Sweden. · Department of Medicine, Helsinki University Hospital, FI-00029 Helsinki, Finland. · Icelandic Heart Association, Kopavogur, Iceland. · Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden. · Laboratory of Epidemiology, Demography, and Biometry, National Institute on Ageing, Bethesda, MD, USA. · Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan. · Cardiovascular Genetics, BHF Laboratories, Institute Cardiovascular Science, University College London, London, United Kingdom. · Cardiovascular Genetics, University of Utah School of Medicine, Salt Lake City, UT, USA. · HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway. · Kaiser Permanente, Division of Research, Oakland, CA, USA. · Unit of Primary Care, Oulu University Hospital, Oulu, Finland. · Department of Chronic Disease Prevention, National Institute for Health and Welfare, Turku, Finland. · Department of Clinical Physiology, University of Tampere School of Medicine, Tampere 33014, Finland. · Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland. · Institute of Clinical Medicine, Department of Medicine, University of Oulu and Clinical Research Center, Oulu University Hospital, Oulu, Finland. · National Heart & Lung Institute, Imperial College London, Hammersmith Hospital, London, United Kingdom. · Children's Hospital Oakland Research Institute, 5700 Martin Luther King Junior Way, Oakland, CA 94609, USA. · Department of Medicine, University of Eastern Finland and Kuopio University Hospital, 70210 Kuopio, Finland. · Institute of Regional Health Services Research, University of Southern Denmark, Odense, Denmark. · Odense Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark. · Institute of Biomedicine/Physiology, University of Eastern Finland, Kuopio Campus, Finland. · Department of Medical Sciences, Uppsala University, Uppsala, Sweden. · Queensland Institute of Medical Research, Locked Bag 2000, Royal Brisbane Hospital, Queensland 4029, Australia. · Synlab Academy, Synlab Services GmbH,Gottlieb-Daimler-Straße 25, 68165 Mannheim, Germany. · Tropical Metabolism Research Unit, Tropical Medicine Research Institute, University of the West Indies, Mona, Kingston 7, Jamaica. · U872 Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, 75006 Paris, France. · Department of Medicine, Kuopio University Hospital, Kuopio, Finland. · Department of Neurology, General Central Hospital, Bolzano, Italy. · Department of Neurology, University of Lübeck, Lübeck, Germany. · Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA, USA. · Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA. · Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland. · Center for Non-Communicable Diseases, Karachi, Pakistan. · Department of Medicine, University of Pennsylvania, USA. · Unit of Chronic Disease Epidemiology and Prevention, National Institute for Health and Welfare, Helsinki, Finland. · South Karelia Central Hospital, Lappeenranta, Finland. · Paul Langerhans Institute Dresden, German Center for Diabetes Research (DZD), Dresden, Germany. · Division of Endocrine and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan. · Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, Maryland. · Faculty of Medicine, University of Iceland, 101 Reykjavík, Iceland. · Division of Population Health Sciences and Education, St George's, University of London, Cranmer Terrace, London SW17 0RE, United Kingdom. · Department of Pharmacological Sciences, University of Milan, Monzino Cardiology Center, IRCCS, Milan, Italy. · Centre for Vascular Prevention, Danube-University Krems, 3500 Krems, Austria. · King Abdulaziz University, Faculty of Medicine, Jeddah 21589, Saudi Arabia. · Red RECAVA Grupo RD06/0014/0015, Hospital Universitario La Paz, 28046. · Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Finland. · Research Unit, Kuopio University Hospital, Kuopio, Finland. · Department of Medicine, Lausanne University Hospital, Switzerland. · Department of Endocrinology, University of Groningen, University Medical Center Groningen, The Netherlands. · Department of Cardiovascular Epidemiology and Population Genetics, National Center for rdiovascular Investigation, Madrid, Spain. · IMDEA-Alimentacion, Madrid, Spain. · Nutrition and Genomics Laboratory, Jean Mayer-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA. · Department of Nutrition, Harvard School of Public Health, Boston, MA, USA. · Framingham Heart Study, Framingham, MA, USA. · Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA. · Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. · Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. ·Nat Genet · Pubmed #24097068.

ABSTRACT: Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.

22 Article Common variants associated with plasma triglycerides and risk for coronary artery disease. 2013

Do, Ron / Willer, Cristen J / Schmidt, Ellen M / Sengupta, Sebanti / Gao, Chi / Peloso, Gina M / Gustafsson, Stefan / Kanoni, Stavroula / Ganna, Andrea / Chen, Jin / Buchkovich, Martin L / Mora, Samia / Beckmann, Jacques S / Bragg-Gresham, Jennifer L / Chang, Hsing-Yi / Demirkan, Ayşe / Den Hertog, Heleen M / Donnelly, Louise A / Ehret, Georg B / Esko, Tõnu / Feitosa, Mary F / Ferreira, Teresa / Fischer, Krista / Fontanillas, Pierre / Fraser, Ross M / Freitag, Daniel F / Gurdasani, Deepti / Heikkilä, Kauko / Hyppönen, Elina / Isaacs, Aaron / Jackson, Anne U / Johansson, Asa / Johnson, Toby / Kaakinen, Marika / Kettunen, Johannes / Kleber, Marcus E / Li, Xiaohui / Luan, Jian'an / Lyytikäinen, Leo-Pekka / Magnusson, Patrik K E / Mangino, Massimo / Mihailov, Evelin / Montasser, May E / Müller-Nurasyid, Martina / Nolte, Ilja M / O'Connell, Jeffrey R / Palmer, Cameron D / Perola, Markus / Petersen, Ann-Kristin / Sanna, Serena / Saxena, Richa / Service, Susan K / Shah, Sonia / Shungin, Dmitry / Sidore, Carlo / Song, Ci / Strawbridge, Rona J / Surakka, Ida / Tanaka, Toshiko / Teslovich, Tanya M / Thorleifsson, Gudmar / Van den Herik, Evita G / Voight, Benjamin F / Volcik, Kelly A / Waite, Lindsay L / Wong, Andrew / Wu, Ying / Zhang, Weihua / Absher, Devin / Asiki, Gershim / Barroso, Inês / Been, Latonya F / Bolton, Jennifer L / Bonnycastle, Lori L / Brambilla, Paolo / Burnett, Mary S / Cesana, Giancarlo / Dimitriou, Maria / Doney, Alex S F / Döring, Angela / Elliott, Paul / Epstein, Stephen E / Eyjolfsson, Gudmundur Ingi / Gigante, Bruna / Goodarzi, Mark O / Grallert, Harald / Gravito, Martha L / Groves, Christopher J / Hallmans, Göran / Hartikainen, Anna-Liisa / Hayward, Caroline / Hernandez, Dena / Hicks, Andrew A / Holm, Hilma / Hung, Yi-Jen / Illig, Thomas / Jones, Michelle R / Kaleebu, Pontiano / Kastelein, John J P / Khaw, Kay-Tee / Kim, Eric / Klopp, Norman / Komulainen, Pirjo / Kumari, Meena / Langenberg, Claudia / Lehtimäki, Terho / Lin, Shih-Yi / Lindström, Jaana / Loos, Ruth J F / Mach, François / McArdle, Wendy L / Meisinger, Christa / Mitchell, Braxton D / Müller, Gabrielle / Nagaraja, Ramaiah / Narisu, Narisu / Nieminen, Tuomo V M / Nsubuga, Rebecca N / Olafsson, Isleifur / Ong, Ken K / Palotie, Aarno / Papamarkou, Theodore / Pomilla, Cristina / Pouta, Anneli / Rader, Daniel J / Reilly, Muredach P / Ridker, Paul M / Rivadeneira, Fernando / Rudan, Igor / Ruokonen, Aimo / Samani, Nilesh / Scharnagl, Hubert / Seeley, Janet / Silander, Kaisa / Stančáková, Alena / Stirrups, Kathleen / Swift, Amy J / Tiret, Laurence / Uitterlinden, Andre G / van Pelt, L Joost / Vedantam, Sailaja / Wainwright, Nicholas / Wijmenga, Cisca / Wild, Sarah H / Willemsen, Gonneke / Wilsgaard, Tom / Wilson, James F / Young, Elizabeth H / Zhao, Jing Hua / Adair, Linda S / Arveiler, Dominique / Assimes, Themistocles L / Bandinelli, Stefania / Bennett, Franklyn / Bochud, Murielle / Boehm, Bernhard O / Boomsma, Dorret I / Borecki, Ingrid B / Bornstein, Stefan R / Bovet, Pascal / Burnier, Michel / Campbell, Harry / Chakravarti, Aravinda / Chambers, John C / Chen, Yii-Der Ida / Collins, Francis S / Cooper, Richard S / Danesh, John / Dedoussis, George / de Faire, Ulf / Feranil, Alan B / Ferrières, Jean / Ferrucci, Luigi / Freimer, Nelson B / Gieger, Christian / Groop, Leif C / Gudnason, Vilmundur / Gyllensten, Ulf / Hamsten, Anders / Harris, Tamara B / Hingorani, Aroon / Hirschhorn, Joel N / Hofman, Albert / Hovingh, G Kees / Hsiung, Chao Agnes / Humphries, Steve E / Hunt, Steven C / Hveem, Kristian / Iribarren, Carlos / Järvelin, Marjo-Riitta / Jula, Antti / Kähönen, Mika / Kaprio, Jaakko / Kesäniemi, Antero / Kivimaki, Mika / Kooner, Jaspal S / Koudstaal, Peter J / Krauss, Ronald M / Kuh, Diana / Kuusisto, Johanna / Kyvik, Kirsten O / Laakso, Markku / Lakka, Timo A / Lind, Lars / Lindgren, Cecilia M / Martin, Nicholas G / März, Winfried / McCarthy, Mark I / McKenzie, Colin A / Meneton, Pierre / Metspalu, Andres / Moilanen, Leena / Morris, Andrew D / Munroe, Patricia B / Njølstad, Inger / Pedersen, Nancy L / Power, Chris / Pramstaller, Peter P / Price, Jackie F / Psaty, Bruce M / Quertermous, Thomas / Rauramaa, Rainer / Saleheen, Danish / Salomaa, Veikko / Sanghera, Dharambir K / Saramies, Jouko / Schwarz, Peter E H / Sheu, Wayne H-H / Shuldiner, Alan R / Siegbahn, Agneta / Spector, Tim D / Stefansson, Kari / Strachan, David P / Tayo, Bamidele O / Tremoli, Elena / Tuomilehto, Jaakko / Uusitupa, Matti / van Duijn, Cornelia M / Vollenweider, Peter / Wallentin, Lars / Wareham, Nicholas J / Whitfield, John B / Wolffenbuttel, Bruce H R / Altshuler, David / Ordovas, Jose M / Boerwinkle, Eric / Palmer, Colin N A / Thorsteinsdottir, Unnur / Chasman, Daniel I / Rotter, Jerome I / Franks, Paul W / Ripatti, Samuli / Cupples, L Adrienne / Sandhu, Manjinder S / Rich, Stephen S / Boehnke, Michael / Deloukas, Panos / Mohlke, Karen L / Ingelsson, Erik / Abecasis, Goncalo R / Daly, Mark J / Neale, Benjamin M / Kathiresan, Sekar. ·1] Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. [3] Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. [4] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA. ·Nat Genet · Pubmed #24097064.

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.

23 Article The shared allelic architecture of adiponectin levels and coronary artery disease. 2013

Dastani, Zari / Johnson, Toby / Kronenberg, Florian / Nelson, Christopher P / Assimes, Themistocles L / März, Winfried / Anonymous5201162 / Anonymous5211162 / Richards, J Brent. ·Department of Epidemiology, Biostatistics and Occupational Health, Jewish General Hospital, Lady Davis Institute, McGill University Montreal, Quebec H3T 1E2, Canada. ·Atherosclerosis · Pubmed #23664276.

ABSTRACT: OBJECTIVE: A large body of epidemiologic data strongly suggests an association between excess adiposity and coronary artery disease (CAD). Low adiponectin levels, a hormone secreted only from adipocytes, have been associated with an increased risk of CAD in observational studies. However, these associations cannot clarify whether this relationship is causal or due to a shared set of causal factors or even confounding. Genome-wide association studies have identified common variants that influence adiponectin levels, providing valuable tools to examine the genetic relationship between adiponectin and CAD. METHODS: Using 145 genome wide significant SNPs for adiponectin from the ADIPOGen consortium (n = 49,891), we tested whether adiponectin-decreasing alleles influenced risk of CAD in the CARDIoGRAM consortium (n = 85,274). RESULTS: In single-SNP analysis, 5 variants among 145 SNPs were associated with increased risk of CAD after correcting for multiple testing (P < 4.4 × 10(-4)). Using a multi-SNP genotypic risk score to test whether adiponectin levels and CAD have a shared genetic etiology, we found that adiponectin-decreasing alleles increased risk of CAD (P = 5.4 × 10(-7)). CONCLUSION: These findings demonstrate that adiponectin levels and CAD have a shared allelic architecture and provide rationale to undertake a Mendelian randomization studies to understand if this relationship is causal.

24 Article A systems biology framework identifies molecular underpinnings of coronary heart disease. 2013

Huan, Tianxiao / Zhang, Bin / Wang, Zhi / Joehanes, Roby / Zhu, Jun / Johnson, Andrew D / Ying, Saixia / Munson, Peter J / Raghavachari, Nalini / Wang, Richard / Liu, Poching / Courchesne, Paul / Hwang, Shih-Jen / Assimes, Themistocles L / McPherson, Ruth / Samani, Nilesh J / Schunkert, Heribert / Anonymous2010754 / Meng, Qingying / Suver, Christine / O'Donnell, Christopher J / Derry, Jonathan / Yang, Xia / Levy, Daniel. ·From the National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA 01702, USA. ·Arterioscler Thromb Vasc Biol · Pubmed #23539213.

ABSTRACT: OBJECTIVE: Genetic approaches have identified numerous loci associated with coronary heart disease (CHD). The molecular mechanisms underlying CHD gene-disease associations, however, remain unclear. We hypothesized that genetic variants with both strong and subtle effects drive gene subnetworks that in turn affect CHD. APPROACH AND RESULTS: We surveyed CHD-associated molecular interactions by constructing coexpression networks using whole blood gene expression profiles from 188 CHD cases and 188 age- and sex-matched controls. Twenty-four coexpression modules were identified, including 1 case-specific and 1 control-specific differential module (DM). The DMs were enriched for genes involved in B-cell activation, immune response, and ion transport. By integrating the DMs with gene expression-associated single-nucleotide polymorphisms and with results of genome-wide association studies of CHD and its risk factors, the control-specific DM was implicated as CHD causal based on its significant enrichment for both CHD and lipid expression-associated single-nucleotide polymorphisms. This causal DM was further integrated with tissue-specific Bayesian networks and protein-protein interaction networks to identify regulatory key driver genes. Multitissue key drivers (SPIB and TNFRSF13C) and tissue-specific key drivers (eg, EBF1) were identified. CONCLUSIONS: Our network-driven integrative analysis not only identified CHD-related genes, but also defined network structure that sheds light on the molecular interactions of genes associated with CHD risk.

25 Article Genetic predisposition to higher blood pressure increases coronary artery disease risk. 2013

Lieb, Wolfgang / Jansen, Henning / Loley, Christina / Pencina, Michael J / Nelson, Christopher P / Newton-Cheh, Christopher / Kathiresan, Sekar / Reilly, Muredach P / Assimes, Themistocles L / Boerwinkle, Eric / Hall, Alistair S / Hengstenberg, Christian / Laaksonen, Reijo / McPherson, Ruth / Thorsteinsdottir, Unnur / Ziegler, Andreas / Peters, Annette / Thompson, John R / König, Inke R / Erdmann, Jeanette / Samani, Nilesh J / Vasan, Ramachandran S / Schunkert, Heribert / Anonymous4971162. ·University Clinic Schleswig Holstein, Institute of Epidemiology, Campus Kiel, Germany. ·Hypertension · Pubmed #23478099.

ABSTRACT: Hypertension is a risk factor for coronary artery disease. Recent genome-wide association studies have identified 30 genetic variants associated with higher blood pressure at genome-wide significance (P<5 × 10(-8)). If elevated blood pressure is a causative factor for coronary artery disease, these variants should also increase coronary artery disease risk. Analyzing genome-wide association data from 22 233 coronary artery disease cases and 64 762 controls, we observed in the Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) consortium that 88% of these blood pressure-associated polymorphisms were likewise positively associated with coronary artery disease, that is, they had an odds ratio >1 for coronary artery disease, a proportion much higher than expected by chance (P=4 × 10(-5)). The average relative coronary artery disease risk increase per each of the multiple blood pressure-raising alleles observed in the consortium was 3.0% for systolic blood pressure-associated polymorphisms (95% confidence interval, 1.8%-4.3%) and 2.9% for diastolic blood pressure-associated polymorphisms (95% confidence interval, 1.7%-4.1%). In substudies, individuals carrying most systolic blood pressure- and diastolic blood pressure-related risk alleles (top quintile of a genetic risk score distribution) had 70% (95% confidence interval, 50%-94%) and 59% (95% confidence interval, 40%-81%) higher odds of having coronary artery disease, respectively, as compared with individuals in the bottom quintile. In conclusion, most blood pressure-associated polymorphisms also confer an increased risk for coronary artery disease. These findings are consistent with a causal relationship of increasing blood pressure to coronary artery disease. Genetic variants primarily affecting blood pressure contribute to the genetic basis of coronary artery disease.

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