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Coronary Artery Disease: HELP
Articles by Stephen E. Epstein
Based on 25 articles published since 2009
(Why 25 articles?)
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Between 2009 and 2019, Stephen E. Epstein wrote the following 25 articles about Coronary Artery Disease.
 
+ Citations + Abstracts
1 Review Percutaneous coronary intervention versus medical therapy in stable coronary artery disease: the unresolved conundrum. 2013

Epstein, Stephen E / Waksman, Ron / Pichard, Augusto D / Kent, Kenneth M / Panza, Julio A. ·MedStar Cardiovascular Research Network, MedStar Heart Institute, MedStar Washington Hospital Center, Washington, DC. Electronic address: stephen.epstein@medstar.net. ·JACC Cardiovasc Interv · Pubmed #24156960.

ABSTRACT: One of the major dilemmas facing physicians is what diagnostic and therapeutic approaches should be recommended to those stable coronary artery disease patients whose symptoms are adequately controlled on medical therapy. This study sought to assess the evidence-based data relating to whether: 1) all patients with significant coronary lesions (i.e., ischemia-producing) should undergo percutaneous coronary intervention (PCI); 2) the best therapeutic approach is optimal medical therapy; or 3) PCI should be performed, but only in certain subsets of patients. We reviewed all recent meta-analyses of prospective randomized trials that compared the outcomes of medical therapy and PCI in stable, symptomatically controlled, coronary artery disease patients. To provide greater insights to the clinician, we then analyzed, in depth, 3 comprehensive and widely quoted randomized trials. Review of recently published (2012) meta-analyses, and the detailed analyses of 3 widely quoted individual studies, indicate no difference exists between PCI and medical therapy in nonfatal MI or in all-cause or cardiovascular mortality. Thus, clinical equipoise exists: in other words, there is no evidence-based justification for adopting 1 therapeutic strategy over the other. Therefore, it is not inappropriate, until additional evidence emerges, for the responsible, experienced physician to weigh several sources of information in formulating a recommendation to the patient, even though definitive evidence-based data are not as yet available. Such sources may include assessment of the individual patient's clinical presentation, assessment of the severity of ischemia, and the patient's precise coronary anatomy. Critical for more-reliable decision making will be future development of accurate measures of the individual patient's risk of MI and/or death, whether by biomarker, imaging, or ischemia assessments.

2 Review Effects of aging on the collateral circulation, and therapeutic implications. 2012

Epstein, Stephen E / Lassance-Soares, Roberta M / Faber, James E / Burnett, Mary Susan. ·Cardiovascular Research Institute, Washington Hospital Center, 110 Irving St, Washington, DC 20010, USA. stephen.epstein@medstar.net ·Circulation · Pubmed #22733335.

ABSTRACT: -- No abstract --

3 Review Insights into the role of infection in atherogenesis and in plaque rupture. 2009

Epstein, Stephen E / Zhu, Jianhui / Najafi, Amir H / Burnett, Mary S. ·Cardiovascular Research Institute, Washington Hospital Center, 110 Irving St NW, Suite 4B-1, Washington, DC 20010, USA. stephen.epstein@medstar.net ·Circulation · Pubmed #19546396.

ABSTRACT: -- No abstract --

4 Article Mechanisms underlying the J-curve for diastolic blood pressure: Subclinical myocardial injury and immune activation. 2019

Topel, Matthew L / Sandesara, Pratik B / Stahl, Eric P / Hayek, Salim S / Tahhan, Ayman Samman / O'Neal, Wesley T / Ko, Yi-An / Alkhoder, Ayman / Gafeer, Mohamad Mazen / Kim, Jonathan H / Wilson, Peter W F / Shaw, Leslee J / Epstein, Stephen E / Vaccarino, Viola / Sperling, Laurence S / Quyyumi, Arshed A. ·Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, Atlanta, GA, United States of America. Electronic address: mtopel@emory.edu. · Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, Atlanta, GA, United States of America. · Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA, United States of America. · MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC, United States of America. · Rollins School of Public Health, Department of Epidemiology, Emory University School of Medicine, Atlanta, GA, United States of America. ·Int J Cardiol · Pubmed #30217423.

ABSTRACT: BACKGROUND: Low diastolic blood pressure (DBP) is associated with increased risk of cardiovascular events. In patients with coronary artery disease (CAD), limitations in coronary blood flow and immune activity are implicated mechanisms, but evidence is lacking. We investigated the association between DBP, biomarkers of myocardial injury, inflammation, immune activation and incident events in patients with CAD. METHODS: We studied 2448 adults (mean age 65 ± 12 years, 68% male, median follow-up 4.5 years) with CAD. DBP was categorized into 10 mm Hg increments. Biomarkers of myocardial injury (high sensitivity cardiac troponin-I [hs-cTnI]) and immune activity/inflammation (soluble urokinase plasminogen activator receptor [suPAR]) were dichotomized at their median values. DBP 70-79 mm Hg was used as the referent group, and individuals were followed prospectively for adverse outcomes. RESULTS: After adjusting for demographic and clinical covariates, individuals with DBP < 60 mm Hg had increased odds of elevated levels of hs-cTnI (OR = 1.68; 95% CI = 1.07, 2.65) and suPAR (OR = 1.71; 95% CI = 1.10, 2.65) compared to the referent group. Additionally, DBP < 60 mm Hg was associated with increased adjusted risk of cardiovascular death or MI (HR = 2.04; 95% CI = 1.32, 3.16) and all-cause mortality (HR = 2.41; 95% CI = 1.69, 3.45). CONCLUSION: In patients with CAD, DBP < 60 mm Hg is associated with subclinical myocardial injury, immune/inflammatory dysregulation and incident events. Aggressive BP control may be harmful in these patients, and further investigation is warranted to determine appropriate BP targets in patients with CAD.

5 Article Comparison of the Association Between High-Sensitivity Troponin I and Adverse Cardiovascular Outcomes in Patients With Versus Without Chronic Kidney Disease. 2018

Sandesara, Pratik B / O'Neal, Wesley T / Tahhan, Ayman Samman / Hayek, Salim S / Lee, Suegene K / Khambhati, Jay / Topel, Matthew L / Hammadah, Muhammad / Alkhoder, Ayman / Ko, Yi-An / Gafeer, Mohamad Mazen / Beshiri, Agim / Murtagh, Gillian / Kim, Jonathan H / Wilson, Peter / Shaw, Leslee / Epstein, Stephen E / Sperling, Laurence S / Quyyumi, Arshed A. ·Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia. Electronic address: psandes@emory.edu. · Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia. · Department of Internal Medicine, Emory University School of Medicine, Atlanta, Georgia. · Department of Biostatistics and Bioinformatics, Emory University, Atlanta, Georgia. · Diagnostics Division, Abbott Laboratories, North Chicago, Illinois. · MedStar Washington Hospital Center, MedStar Heart and Vascular Institute, Washington, District of Columbia. ·Am J Cardiol · Pubmed #29628129.

ABSTRACT: It is unknown whether the association of high-sensitivity troponin I (hs-TnI) with adverse cardiovascular outcomes varies by the presence of chronic kidney disease (CKD). We examined the association of hs-TnI with adverse cardiovascular outcomes in those with and without CKD in 4,107 (mean age, 64 years; 63% men; 20% black) patients from the Emory Cardiovascular Biobank who underwent coronary angiography. CKD (n = 1,073) was defined as estimated glomerular filtration rate <60 ml/min/1.73 m

6 Article An Aggregate Biomarker Risk Score Predicts High Risk of Near-Term Myocardial Infarction and Death: Findings From BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes). 2017

Ghasemzadeh, Nima / Brooks, Maria M / Vlachos, Helen / Hardison, Regina / Sikora, Sergey / Sperling, Laurence / Quyyumi, Arshed A / Epstein, Stephen E. ·Emory University School of Medicine, Atlanta, GA. · Graduate School of Public Health, University of Pittsburgh, PA. · CardioCell, San Diego, CA. · Emory University School of Medicine, Atlanta, GA aquyyum@emory.edu. · MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC. ·J Am Heart Assoc · Pubmed #28673897.

ABSTRACT: BACKGROUND: In a previous study, we found that a biomarker risk score (BRS) comprised of C-reactive protein, fibrin-degradation products, and heat shock protein-70 predicts risk of myocardial infarction and death in coronary artery disease patients. We sought to: (1) validate the BRS in the independent BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) cohort, (2) investigate whether 1 year of intensive medical therapy is associated with improved BRS, and (3) elucidate whether an altered BRS parallels altered risk. METHODS AND RESULTS: Two thousand thirty-two subjects with coronary artery disease were followed for 5.3±1.1 years for cardiovascular events. Biomarkers were measured at baseline and retested in 1304 subjects at 1 year. BRS was determined as the biomarker number above previously defined cut-off values (C-reactive protein >3 mg/L, heat shock protein-70 >0.313 ng/mL, and fibrin-degradation products >1 μg/mL). After adjustment for covariates, those with a BRS of 3 had a 4-fold increased risk of all-cause death and a 6.8-fold increased risk of cardiac death compared with those with a BRS of 0 (95% CI, 2.9-16.0; CONCLUSIONS: Our results validate the ability of the BRS to identify coronary artery disease patients at very high near-term risk of myocardial infarction/death. After 1 year of intensive medical therapy, the BRS decreased significantly, and the reclassified BRS continued to track with risk. Our results suggest that repeated BRS measurements might be used to assess risk and recalibrate therapy.

7 Article Pathway-Specific Aggregate Biomarker Risk Score Is Associated With Burden of Coronary Artery Disease and Predicts Near-Term Risk of Myocardial Infarction and Death. 2017

Ghasemzedah, Nima / Hayek, Salim S / Ko, Yi-An / Eapen, Danny J / Patel, Riyaz S / Manocha, Pankaj / Al Kassem, Hatem / Khayata, Mohamed / Veledar, Emir / Kremastinos, Dimitrios / Thorball, Christian W / Pielak, Tomasz / Sikora, Sergey / Zafari, A Maziar / Lerakis, Stamatios / Sperling, Laurence / Vaccarino, Viola / Epstein, Stephen E / Quyyumi, Arshed A. ·From the Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA (N.G., S.S.H., D.J.E., R.S.P., P.M., H.A.K., M.K., E.V., A.M.Z., S.L., L.S., V.V., A.A.Q.) · Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.) · Institute of Cardiovascular Science, University College London, United Kingdom (R.S.P.) · Division of Cardiology, Atlanta VA Medical Center, GA (A.M.Z.) · Department of Biostatistics, Florida International University, Miami (E.V.) · Department of Cardiology, University of Athens School of Medicine, Greece (D.K.) · Clinical Research Centre, Copenhagen University Hospital, Denmark (C.W.T., T.P.) · Stemedica Cell Technologies, Inc., San Diego, CA (S.S.) · Department of Epidemiology, Emory University, Atlanta, GA (V.V.) · and MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E.). ·Circ Cardiovasc Qual Outcomes · Pubmed #28280039.

ABSTRACT: BACKGROUND: Inflammation, coagulation, and cell stress contribute to atherosclerosis and its adverse events. A biomarker risk score (BRS) based on the circulating levels of biomarkers C-reactive protein, fibrin degradation products, and heat shock protein-70 representing these 3 pathways was a strong predictor of future outcomes. We investigated whether soluble urokinase plasminogen activator receptor (suPAR), a marker of immune activation, is predictive of outcomes independent of the aforementioned markers and whether its addition to a 3-BRS improves risk reclassification. METHODS AND RESULTS: C-reactive protein, fibrin degradation product, heat shock protein-70, and suPAR were measured in 3278 patients undergoing coronary angiography. The BRS was calculated by counting the number of biomarkers above a cutoff determined using the Youden's index. Survival analyses were performed using models adjusted for traditional risk factors. A high suPAR level ≥3.5 ng/mL was associated with all-cause death and myocardial infarction (hazard ratio, 1.83; 95% confidence interval, 1.43-2.35) after adjustment for risk factors, C-reactive protein, fibrin degradation product, and heat shock protein-70. Addition of suPAR to the 3-BRS significantly improved the C statistic, integrated discrimination improvement, and net reclassification index for the primary outcome. A BRS of 1, 2, 3, or 4 was associated with a 1.81-, 2.59-, 6.17-, and 8.80-fold increase, respectively, in the risk of death and myocardial infarction. The 4-BRS was also associated with severity of coronary artery disease and composite end points. CONCLUSIONS: SuPAR is independently predictive of adverse outcomes, and its addition to a 3-BRS comprising C-reactive protein, fibrin degradation product, and heat shock protein-70 improved risk reclassification. The clinical utility of using a 4-BRS for risk prediction and management of patients with coronary artery disease warrants further study.

8 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.

9 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.

10 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.

11 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.

12 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.

13 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.

14 Article Aggregate risk score based on markers of inflammation, cell stress, and coagulation is an independent predictor of adverse cardiovascular outcomes. 2013

Eapen, Danny J / Manocha, Pankaj / Patel, Riyaz S / Hammadah, Muhammad / Veledar, Emir / Wassel, Christina / Nanjundappa, Ravi A / Sikora, Sergey / Malayter, Dylan / Wilson, Peter W F / Sperling, Laurence / Quyyumi, Arshed A / Epstein, Stephen E. ·Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA 30322, USA. ·J Am Coll Cardiol · Pubmed #23665099.

ABSTRACT: OBJECTIVES: This study sought to determine an aggregate, pathway-specific risk score for enhanced prediction of death and myocardial infarction (MI). BACKGROUND: Activation of inflammatory, coagulation, and cellular stress pathways contribute to atherosclerotic plaque rupture. We hypothesized that an aggregate risk score comprised of biomarkers involved in these different pathways-high-sensitivity C-reactive protein (CRP), fibrin degradation products (FDP), and heat shock protein 70 (HSP70) levels-would be a powerful predictor of death and MI. METHODS: Serum levels of CRP, FDP, and HSP70 were measured in 3,415 consecutive patients with suspected or confirmed coronary artery disease (CAD) undergoing cardiac catheterization. Survival analyses were performed with models adjusted for established risk factors. RESULTS: Median follow-up was 2.3 years. Hazard ratios (HRs) for all-cause death and MI based on cutpoints were as follows: CRP ≥3.0 mg/l, HR: 1.61; HSP70 >0.625 ng/ml, HR; 2.26; and FDP ≥1.0 μg/ml, HR: 1.62 (p < 0.0001 for all). An aggregate biomarker score between 0 and 3 was calculated based on these cutpoints. Compared with the group with a 0 score, HRs for all-cause death and MI were 1.83, 3.46, and 4.99 for those with scores of 1, 2, and 3, respectively (p for each: <0.001). Annual event rates were 16.3% for the 4.2% of patients with a score of 3 compared with 2.4% in 36.4% of patients with a score of 0. The C statistic and net reclassification improved (p < 0.0001) with the addition of the biomarker score. CONCLUSIONS: An aggregate score based on serum levels of CRP, FDP, and HSP70 is a predictor of future risk of death and MI in patients with suspected or known CAD.

15 Article Association between the chromosome 9p21 locus and angiographic coronary artery disease burden: a collaborative meta-analysis. 2013

Chan, Kenneth / Patel, Riyaz S / Newcombe, Paul / Nelson, Christopher P / Qasim, Atif / Epstein, Stephen E / Burnett, Susan / Vaccarino, Viola L / Zafari, A Maziar / Shah, Svati H / Anderson, Jeffrey L / Carlquist, John F / Hartiala, Jaana / Allayee, Hooman / Hinohara, Kunihiko / Lee, Bok-Soo / Erl, Anna / Ellis, Katrina L / Goel, Anuj / Schaefer, Arne S / El Mokhtari, Nour Eddine / Goldstein, Benjamin A / Hlatky, Mark A / Go, Alan S / Shen, Gong-Qing / Gong, Yan / Pepine, Carl / Laxton, Ross C / Whittaker, John C / Tang, W H Wilson / Johnson, Julie A / Wang, Qing K / Assimes, Themistocles L / Nöthlings, Ute / Farrall, Martin / Watkins, Hugh / Richards, A Mark / Cameron, Vicky A / Muendlein, Axel / Drexel, Heinz / Koch, Werner / Park, Jeong Euy / Kimura, Akinori / Shen, Wei-feng / Simpson, Iain A / Hazen, Stanley L / Horne, Benjamin D / Hauser, Elizabeth R / Quyyumi, Arshed A / Reilly, Muredach P / Samani, Nilesh J / Ye, Shu. ·William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University London, London, United Kingdom. ·J Am Coll Cardiol · Pubmed #23352782.

ABSTRACT: OBJECTIVES: This study sought to ascertain the relationship of 9p21 locus with: 1) angiographic coronary artery disease (CAD) burden; and 2) myocardial infarction (MI) in individuals with underlying CAD. BACKGROUND: Chromosome 9p21 variants have been robustly associated with coronary heart disease, but questions remain on the mechanism of risk, specifically whether the locus contributes to coronary atheroma burden or plaque instability. METHODS: We established a collaboration of 21 studies consisting of 33,673 subjects with information on both CAD (clinical or angiographic) and MI status along with 9p21 genotype. Tabular data are provided for each cohort on the presence and burden of angiographic CAD, MI cases with underlying CAD, and the diabetic status of all subjects. RESULTS: We first confirmed an association between 9p21 and CAD with angiographically defined cases and control subjects (pooled odds ratio [OR]: 1.31, 95% confidence interval [CI]: 1.20 to 1.43). Among subjects with angiographic CAD (n = 20,987), random-effects model identified an association with multivessel CAD, compared with those with single-vessel disease (OR: 1.10, 95% CI: 1.04 to 1.17)/copy of risk allele). Genotypic models showed an OR of 1.15, 95% CI: 1.04 to 1.26 for heterozygous carrier and OR: 1.23, 95% CI: 1.08 to 1.39 for homozygous carrier. Finally, there was no significant association between 9p21 and prevalent MI when both cases (n = 17,791) and control subjects (n = 15,882) had underlying CAD (OR: 0.99, 95% CI: 0.95 to 1.03)/risk allele. CONCLUSIONS: The 9p21 locus shows convincing association with greater burden of CAD but not with MI in the presence of underlying CAD. This adds further weight to the hypothesis that 9p21 locus primarily mediates an atherosclerotic phenotype.

16 Article Large-scale association analysis identifies new risk loci for coronary artery disease. 2013

Anonymous5600743 / Deloukas, Panos / Kanoni, Stavroula / Willenborg, Christina / Farrall, Martin / Assimes, Themistocles L / Thompson, John R / Ingelsson, Erik / Saleheen, Danish / Erdmann, Jeanette / Goldstein, Benjamin A / Stirrups, Kathleen / König, Inke R / Cazier, Jean-Baptiste / Johansson, Asa / Hall, Alistair S / Lee, Jong-Young / Willer, Cristen J / Chambers, John C / Esko, Tõnu / Folkersen, Lasse / Goel, Anuj / Grundberg, Elin / Havulinna, Aki S / Ho, Weang K / Hopewell, Jemma C / Eriksson, Niclas / Kleber, Marcus E / Kristiansson, Kati / Lundmark, Per / Lyytikäinen, Leo-Pekka / Rafelt, Suzanne / Shungin, Dmitry / Strawbridge, Rona J / Thorleifsson, Gudmar / Tikkanen, Emmi / Van Zuydam, Natalie / Voight, Benjamin F / Waite, Lindsay L / Zhang, Weihua / Ziegler, Andreas / Absher, Devin / Altshuler, David / Balmforth, Anthony J / Barroso, Inês / Braund, Peter S / Burgdorf, Christof / Claudi-Boehm, Simone / Cox, David / Dimitriou, Maria / Do, Ron / Anonymous5610743 / Anonymous5620743 / Doney, Alex S F / El Mokhtari, NourEddine / Eriksson, Per / Fischer, Krista / Fontanillas, Pierre / Franco-Cereceda, Anders / Gigante, Bruna / Groop, Leif / Gustafsson, Stefan / Hager, Jörg / Hallmans, Göran / Han, Bok-Ghee / Hunt, Sarah E / Kang, Hyun M / Illig, Thomas / Kessler, Thorsten / Knowles, Joshua W / Kolovou, Genovefa / Kuusisto, Johanna / Langenberg, Claudia / Langford, Cordelia / Leander, Karin / Lokki, Marja-Liisa / Lundmark, Anders / McCarthy, Mark I / Meisinger, Christa / Melander, Olle / Mihailov, Evelin / Maouche, Seraya / Morris, Andrew D / Müller-Nurasyid, Martina / Anonymous5630743 / Nikus, Kjell / Peden, John F / Rayner, N William / Rasheed, Asif / Rosinger, Silke / Rubin, Diana / Rumpf, Moritz P / Schäfer, Arne / Sivananthan, Mohan / Song, Ci / Stewart, Alexandre F R / Tan, Sian-Tsung / Thorgeirsson, Gudmundur / van der Schoot, C Ellen / Wagner, Peter J / Anonymous5640743 / Wells, George A / Wild, Philipp S / Yang, Tsun-Po / Amouyel, Philippe / Arveiler, Dominique / Basart, Hanneke / Boehnke, Michael / Boerwinkle, Eric / Brambilla, Paolo / Cambien, Francois / Cupples, Adrienne L / de Faire, Ulf / Dehghan, Abbas / Diemert, Patrick / Epstein, Stephen E / Evans, Alun / Ferrario, Marco M / Ferrières, Jean / Gauguier, Dominique / Go, Alan S / Goodall, Alison H / Gudnason, Villi / Hazen, Stanley L / Holm, Hilma / Iribarren, Carlos / Jang, Yangsoo / Kähönen, Mika / Kee, Frank / Kim, Hyo-Soo / Klopp, Norman / Koenig, Wolfgang / Kratzer, Wolfgang / Kuulasmaa, Kari / Laakso, Markku / Laaksonen, Reijo / Lee, Ji-Young / Lind, Lars / Ouwehand, Willem H / Parish, Sarah / Park, Jeong E / Pedersen, Nancy L / Peters, Annette / Quertermous, Thomas / Rader, Daniel J / Salomaa, Veikko / Schadt, Eric / Shah, Svati H / Sinisalo, Juha / Stark, Klaus / Stefansson, Kari / Trégouët, David-Alexandre / Virtamo, Jarmo / Wallentin, Lars / Wareham, Nicholas / Zimmermann, Martina E / Nieminen, Markku S / Hengstenberg, Christian / Sandhu, Manjinder S / Pastinen, Tomi / Syvänen, Ann-Christine / Hovingh, G Kees / Dedoussis, George / Franks, Paul W / Lehtimäki, Terho / Metspalu, Andres / Zalloua, Pierre A / Siegbahn, Agneta / Schreiber, Stefan / Ripatti, Samuli / Blankenberg, Stefan S / Perola, Markus / Clarke, Robert / Boehm, Bernhard O / O'Donnell, Christopher / Reilly, Muredach P / März, Winfried / Collins, Rory / Kathiresan, Sekar / Hamsten, Anders / Kooner, Jaspal S / Thorsteinsdottir, Unnur / Danesh, John / Palmer, Colin N A / Roberts, Robert / Watkins, Hugh / Schunkert, Heribert / Samani, Nilesh J. · ·Nat Genet · Pubmed #23202125.

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

17 Article Polymorphisms in dipeptidyl peptidase IV gene are associated with the risk of myocardial infarction in patients with atherosclerosis. 2012

Aghili, Nima / Devaney, Joseph M / Alderman, Lee O / Zukowska, Zofia / Epstein, Stephen E / Burnett, Mary Susan. ·Tufts Medical Center, Department of Cardiovascular Disease, 800 Washington St., Boston, MA, United States. naghili@tuftsmedicalcenter.org ·Neuropeptides · Pubmed #23122333.

ABSTRACT: BACKGROUND: Dipeptidyl peptidase IV (DPP-IV) is not only important in pancreatic β-cell regulation but also has proinflammatory actions that can contribute to atherosclerosis progression. Previously, we showed that DPP-IV is co-localized with CD31 (an endothelial cell marker) in the neovessels within the human atherosclerotic plaques. These characteristics of DPP-IV may predispose patients with coronary artery disease (CAD) to plaque rupture and thus to myocardial infarction. The goal of this investigation was to determine whether genetic alterations in DPP-IV predispose to plaque vulnerability and myocardial infarction (MI). METHODS: Between Aug 2004, and March 2007, blood samples of patients (age <60) with angiographically documented CAD were collected. Demographic, clinical, risk factor, and angiographic data were recorded. Eight hundred and seventy five patients of European ancestry with angiographic CAD were divided into those with MI (n=421) and those without (n=454). A genome-wide association study was performed using the Affymetrix 6.0 chip to identify loci that predispose to MI. In the current study we only focused on DPP4 gene to assess the association of single nucleotide polymorphisms (SNPs) in the DPP-IV gene and risk of MI in patients with CAD. For genotyped SNPs, association was tested by logistic regression with significance level of 0.05. Plasma DPP-IV level was measured using a commercial ELISA kit. RESULTS: Average patients' age at diagnosis of CAD was 46.8years for MI group and 50.8 in the non MI group. There was no difference in distribution of traditional risk factors between the two groups. We identified one SNP (rs3788979) that was significantly related to angiographic CAD with MI, vs. without MI (OR: 1.36, p=0.03). The association of the identified SNP to MI risk was not attenuated after adjustment for traditional risk factors. The SNP was associated with lower levels of plasma DPP-IV (p=0.005). Moreover, CAD patients with the major alleles (GG) and no MI had highest plasma DPP-IV levels. (481.6, p=0.002). CONCLUSIONS: A polymorphism in the DPP-IV gene in patients with known CAD may increase the risk of MI. This SNP is associated with decreased plasma DPP4 level in patients with MI.

18 Article A genome-wide association study for coronary artery disease identifies a novel susceptibility locus in the major histocompatibility complex. 2012

Davies, Robert W / Wells, George A / Stewart, Alexandre F R / Erdmann, Jeanette / Shah, Svati H / Ferguson, Jane F / Hall, Alistair S / Anand, Sonia S / Burnett, Mary S / Epstein, Stephen E / Dandona, Sonny / Chen, Li / Nahrstaedt, Janja / Loley, Christina / König, Inke R / Kraus, William E / Granger, Christopher B / Engert, James C / Hengstenberg, Christian / Wichmann, H-Erich / Schreiber, Stefan / Tang, W H Wilson / Ellis, Stephen G / Rader, Daniel J / Hazen, Stanley L / Reilly, Muredach P / Samani, Nilesh J / Schunkert, Heribert / Roberts, Robert / McPherson, Ruth. ·Cardiovascular Research Methods Center, John and Jennifer Ruddy Canadian Cardiovascular Research Center, University of Ottawa Heart Institute, Ottawa, ON, Canada. rwdavies@well.ox.ac.uk ·Circ Cardiovasc Genet · Pubmed #22319020.

ABSTRACT: BACKGROUND: Recent genome-wide association studies (GWAS) have identified several novel loci that reproducibly associate with coronary artery disease (CAD) and/or myocardial infarction risk. However, known common CAD risk variants explain only 10% of the predicted genetic heritability of the disease, suggesting that important genetic signals remain to be discovered. METHODS AND RESULTS: We performed a discovery meta-analysis of 5 GWAS involving 13 949 subjects (7123 cases, 6826 control subjects) imputed at approximately 5 million single nucleotide polymorphisms, using pilot 1000 Genomes-based haplotypes. Promising loci were followed up in an additional 5 studies with 11 032 subjects (5211 cases, 5821 control subjects). A novel CAD locus on chromosome 6p21.3 in the major histocompatibility complex (MHC) between HCG27 and HLA-C was identified and achieved genome-wide significance in the combined analysis (rs3869109; p(discovery)=3.3×10(-7), p(replication)=5.3×10(-4)p(combined)=1.12×10(-9)). A subanalysis combining discovery GWAS showed an attenuation of significance when stringent corrections for European population structure were used (P=4.1×10(-10) versus 3.2×10(-7)), suggesting that the observed signal is partly confounded due to population stratification. This gene dense region plays an important role in inflammation, immunity, and self-cell recognition. To determine whether the underlying association was driven by MHC class I alleles, we statistically imputed common HLA alleles into the discovery subjects; however, no single common HLA type contributed significantly or fully explained the observed association. CONCLUSIONS: We have identified a novel locus in the MHC associated with CAD. MHC genes regulate inflammation and T-cell responses that contribute importantly to the initiation and propagation of atherosclerosis. Further laboratory studies will be required to understand the biological basis of this association and identify the causative allele(s).

19 Article A genome-wide association study identifies LIPA as a susceptibility gene for coronary artery disease. 2011

Wild, Philipp S / Zeller, Tanja / Schillert, Arne / Szymczak, Silke / Sinning, Christoph R / Deiseroth, Arne / Schnabel, Renate B / Lubos, Edith / Keller, Till / Eleftheriadis, Medea S / Bickel, Christoph / Rupprecht, Hans J / Wilde, Sandra / Rossmann, Heidi / Diemert, Patrick / Cupples, L Adrienne / Perret, Claire / Erdmann, Jeanette / Stark, Klaus / Kleber, Marcus E / Epstein, Stephen E / Voight, Benjamin F / Kuulasmaa, Kari / Li, Mingyao / Schäfer, Arne S / Klopp, Norman / Braund, Peter S / Sager, Hendrik B / Demissie, Serkalem / Proust, Carole / König, Inke R / Wichmann, Heinz-Erich / Reinhard, Wibke / Hoffmann, Michael M / Virtamo, Jarmo / Burnett, Mary Susan / Siscovick, David / Wiklund, Per Gunnar / Qu, Liming / El Mokthari, Nour Eddine / Thompson, John R / Peters, Annette / Smith, Albert V / Yon, Emmanuelle / Baumert, Jens / Hengstenberg, Christian / März, Winfried / Amouyel, Philippe / Devaney, Joseph / Schwartz, Stephen M / Saarela, Olli / Mehta, Nehal N / Rubin, Diana / Silander, Kaisa / Hall, Alistair S / Ferrieres, Jean / Harris, Tamara B / Melander, Olle / Kee, Frank / Hakonarson, Hakon / Schrezenmeir, Juergen / Gudnason, Vilmundur / Elosua, Roberto / Arveiler, Dominique / Evans, Alun / Rader, Daniel J / Illig, Thomas / Schreiber, Stefan / Bis, Joshua C / Altshuler, David / Kavousi, Maryam / Witteman, Jaqueline C M / Uitterlinden, Andre G / Hofman, Albert / Folsom, Aaron R / Barbalic, Maja / Boerwinkle, Eric / Kathiresan, Sekar / Reilly, Muredach P / O'Donnell, Christopher J / Samani, Nilesh J / Schunkert, Heribert / Cambien, Francois / Lackner, Karl J / Tiret, Laurence / Salomaa, Veikko / Munzel, Thomas / Ziegler, Andreas / Blankenberg, Stefan. ·Department of Medicine II, University Medical Center Mainz, Germany. ·Circ Cardiovasc Genet · Pubmed #21606135.

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

20 Article Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. 2011

Schunkert, Heribert / König, Inke R / Kathiresan, Sekar / Reilly, Muredach P / Assimes, Themistocles L / Holm, Hilma / Preuss, Michael / Stewart, Alexandre F R / Barbalic, Maja / Gieger, Christian / Absher, Devin / Aherrahrou, Zouhair / Allayee, Hooman / Altshuler, David / Anand, Sonia S / Andersen, Karl / Anderson, Jeffrey L / Ardissino, Diego / Ball, Stephen G / Balmforth, Anthony J / Barnes, Timothy A / Becker, Diane M / Becker, Lewis C / Berger, Klaus / Bis, Joshua C / Boekholdt, S Matthijs / Boerwinkle, Eric / Braund, Peter S / Brown, Morris J / Burnett, Mary Susan / Buysschaert, Ian / Anonymous3291162 / Carlquist, John F / Chen, Li / Cichon, Sven / Codd, Veryan / Davies, Robert W / Dedoussis, George / Dehghan, Abbas / Demissie, Serkalem / Devaney, Joseph M / Diemert, Patrick / Do, Ron / Doering, Angela / Eifert, Sandra / Mokhtari, Nour Eddine El / Ellis, Stephen G / Elosua, Roberto / Engert, James C / Epstein, Stephen E / de Faire, Ulf / Fischer, Marcus / Folsom, Aaron R / Freyer, Jennifer / Gigante, Bruna / Girelli, Domenico / Gretarsdottir, Solveig / Gudnason, Vilmundur / Gulcher, Jeffrey R / Halperin, Eran / Hammond, Naomi / Hazen, Stanley L / Hofman, Albert / Horne, Benjamin D / Illig, Thomas / Iribarren, Carlos / Jones, Gregory T / Jukema, J Wouter / Kaiser, Michael A / Kaplan, Lee M / Kastelein, John J P / Khaw, Kay-Tee / Knowles, Joshua W / Kolovou, Genovefa / Kong, Augustine / Laaksonen, Reijo / Lambrechts, Diether / Leander, Karin / Lettre, Guillaume / Li, Mingyao / Lieb, Wolfgang / Loley, Christina / Lotery, Andrew J / Mannucci, Pier M / Maouche, Seraya / Martinelli, Nicola / McKeown, Pascal P / Meisinger, Christa / Meitinger, Thomas / Melander, Olle / Merlini, Pier Angelica / Mooser, Vincent / Morgan, Thomas / Mühleisen, Thomas W / Muhlestein, Joseph B / Münzel, Thomas / Musunuru, Kiran / Nahrstaedt, Janja / Nelson, Christopher P / Nöthen, Markus M / Olivieri, Oliviero / Patel, Riyaz S / Patterson, Chris C / Peters, Annette / Peyvandi, Flora / Qu, Liming / Quyyumi, Arshed A / Rader, Daniel J / Rallidis, Loukianos S / Rice, Catherine / Rosendaal, Frits R / Rubin, Diana / Salomaa, Veikko / Sampietro, M Lourdes / Sandhu, Manj S / Schadt, Eric / Schäfer, Arne / Schillert, Arne / Schreiber, Stefan / Schrezenmeir, Jürgen / Schwartz, Stephen M / Siscovick, David S / Sivananthan, Mohan / Sivapalaratnam, Suthesh / Smith, Albert / Smith, Tamara B / Snoep, Jaapjan D / Soranzo, Nicole / Spertus, John A / Stark, Klaus / Stirrups, Kathy / Stoll, Monika / Tang, W H Wilson / Tennstedt, Stephanie / Thorgeirsson, Gudmundur / Thorleifsson, Gudmar / Tomaszewski, Maciej / Uitterlinden, Andre G / van Rij, Andre M / Voight, Benjamin F / Wareham, Nick J / Wells, George A / Wichmann, H-Erich / Wild, Philipp S / Willenborg, Christina / Witteman, Jaqueline C M / Wright, Benjamin J / Ye, Shu / Zeller, Tanja / Ziegler, Andreas / Cambien, Francois / Goodall, Alison H / Cupples, L Adrienne / Quertermous, Thomas / März, Winfried / Hengstenberg, Christian / Blankenberg, Stefan / Ouwehand, Willem H / Hall, Alistair S / Deloukas, Panos / Thompson, John R / Stefansson, Kari / Roberts, Robert / Thorsteinsdottir, Unnur / O'Donnell, Christopher J / McPherson, Ruth / Erdmann, Jeanette / Anonymous3301162 / Samani, Nilesh J. ·Universität zu Lübeck, Medizinische Klinik II, Lübeck, Germany. ·Nat Genet · Pubmed #21378990.

ABSTRACT: We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 × 10⁻⁸ and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.

21 Article Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies. 2011

Reilly, Muredach P / Li, Mingyao / He, Jing / Ferguson, Jane F / Stylianou, Ioannis M / Mehta, Nehal N / Burnett, Mary Susan / Devaney, Joseph M / Knouff, Christopher W / Thompson, John R / Horne, Benjamin D / Stewart, Alexandre F R / Assimes, Themistocles L / Wild, Philipp S / Allayee, Hooman / Nitschke, Patrick Linsel / Patel, Riyaz S / Anonymous500684 / Anonymous510684 / Martinelli, Nicola / Girelli, Domenico / Quyyumi, Arshed A / Anderson, Jeffrey L / Erdmann, Jeanette / Hall, Alistair S / Schunkert, Heribert / Quertermous, Thomas / Blankenberg, Stefan / Hazen, Stanley L / Roberts, Robert / Kathiresan, Sekar / Samani, Nilesh J / Epstein, Stephen E / Rader, Daniel J. ·Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104-6160, USA. muredach@mail.med.upenn.edu ·Lancet · Pubmed #21239051.

ABSTRACT: BACKGROUND: We tested whether genetic factors distinctly contribute to either development of coronary atherosclerosis or, specifically, to myocardial infarction in existing coronary atherosclerosis. METHODS: We did two genome-wide association studies (GWAS) with coronary angiographic phenotyping in participants of European ancestry. To identify loci that predispose to angiographic coronary artery disease (CAD), we compared individuals who had this disorder (n=12,393) with those who did not (controls, n=7383). To identify loci that predispose to myocardial infarction, we compared patients who had angiographic CAD and myocardial infarction (n=5783) with those who had angiographic CAD but no myocardial infarction (n=3644). FINDINGS: In the comparison of patients with angiographic CAD versus controls, we identified a novel locus, ADAMTS7 (p=4·98×10(-13)). In the comparison of patients with angiographic CAD who had myocardial infarction versus those with angiographic CAD but no myocardial infarction, we identified a novel association at the ABO locus (p=7·62×10(-9)). The ABO association was attributable to the glycotransferase-deficient enzyme that encodes the ABO blood group O phenotype previously proposed to protect against myocardial infarction. INTERPRETATION: Our findings indicate that specific genetic predispositions promote the development of coronary atherosclerosis whereas others lead to myocardial infarction in the presence of coronary atherosclerosis. The relation to specific CAD phenotypes might modify how novel loci are applied in personalised risk assessment and used in the development of novel therapies for CAD. FUNDING: The PennCath and MedStar studies were supported by the Cardiovascular Institute of the University of Pennsylvania, by the MedStar Health Research Institute at Washington Hospital Center and by a research grant from GlaxoSmithKline. The funding and support for the other cohorts contributing to the paper are described in the webappendix.

22 Article Lack of association between the Trp719Arg polymorphism in kinesin-like protein-6 and coronary artery disease in 19 case-control studies. 2010

Assimes, Themistocles L / Hólm, Hilma / Kathiresan, Sekar / Reilly, Muredach P / Thorleifsson, Gudmar / Voight, Benjamin F / Erdmann, Jeanette / Willenborg, Christina / Vaidya, Dhananjay / Xie, Changchun / Patterson, Chris C / Morgan, Thomas M / Burnett, Mary Susan / Li, Mingyao / Hlatky, Mark A / Knowles, Joshua W / Thompson, John R / Absher, Devin / Iribarren, Carlos / Go, Alan / Fortmann, Stephen P / Sidney, Stephen / Risch, Neil / Tang, Hua / Myers, Richard M / Berger, Klaus / Stoll, Monika / Shah, Svati H / Thorgeirsson, Gudmundur / Andersen, Karl / Havulinna, Aki S / Herrera, J Enrique / Faraday, Nauder / Kim, Yoonhee / Kral, Brian G / Mathias, Rasika A / Ruczinski, Ingo / Suktitipat, Bhoom / Wilson, Alexander F / Yanek, Lisa R / Becker, Lewis C / Linsel-Nitschke, Patrick / Lieb, Wolfgang / König, Inke R / Hengstenberg, Christian / Fischer, Marcus / Stark, Klaus / Reinhard, Wibke / Winogradow, Janina / Grassl, Martina / Grosshennig, Anika / Preuss, Michael / Schreiber, Stefan / Wichmann, H-Erich / Meisinger, Christa / Yee, Jean / Friedlander, Yechiel / Do, Ron / Meigs, James B / Williams, Gordon / Nathan, David M / MacRae, Calum A / Qu, Liming / Wilensky, Robert L / Matthai, William H / Qasim, Atif N / Hakonarson, Hakon / Pichard, Augusto D / Kent, Kenneth M / Satler, Lowell / Lindsay, Joseph M / Waksman, Ron / Knouff, Christopher W / Waterworth, Dawn M / Walker, Max C / Mooser, Vincent E / Marrugat, Jaume / Lucas, Gavin / Subirana, Isaac / Sala, Joan / Ramos, Rafael / Martinelli, Nicola / Olivieri, Oliviero / Trabetti, Elisabetta / Malerba, Giovanni / Pignatti, Pier Franco / Guiducci, Candace / Mirel, Daniel / Parkin, Melissa / Hirschhorn, Joel N / Asselta, Rosanna / Duga, Stefano / Musunuru, Kiran / Daly, Mark J / Purcell, Shaun / Eifert, Sandra / Braund, Peter S / Wright, Benjamin J / Balmforth, Anthony J / Ball, Stephen G / Anonymous2921162 / Anonymous2931162 / Anonymous2941162 / Ouwehand, Willem H / Deloukas, Panos / Scholz, Michael / Cambien, Francois / Huge, Andreas / Scheffold, Thomas / Salomaa, Veikko / Girelli, Domenico / Granger, Christopher B / Peltonen, Leena / McKeown, Pascal P / Altshuler, David / Melander, Olle / Devaney, Joseph M / Epstein, Stephen E / Rader, Daniel J / Elosua, Roberto / Engert, James C / Anand, Sonia S / Hall, Alistair S / Ziegler, Andreas / O'Donnell, Christopher J / Spertus, John A / Siscovick, David / Schwartz, Stephen M / Becker, Diane / Thorsteinsdottir, Unnur / Stefansson, Kari / Schunkert, Heribert / Samani, Nilesh J / Quertermous, Thomas. ·Department of Medicine, Stanford University School of Medicine, Stanford, California 94304-1334, USA. tassimes@stanford.edu ·J Am Coll Cardiol · Pubmed #20933357.

ABSTRACT: OBJECTIVES: We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455), and clinical coronary artery disease (CAD). BACKGROUND: Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with noncarriers. METHODS: The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in 19 case-control studies of nonfatal CAD either as part of a genome-wide association study or in a formal attempt to replicate the initial positive reports. RESULTS: A total of 17,000 cases and 39,369 controls of European descent as well as a modest number of South Asians, African Americans, Hispanics, East Asians, and admixed cases and controls were successfully genotyped. None of the 19 studies demonstrated an increased risk of CAD in carriers of the 719Arg allele compared with noncarriers. Regression analyses and fixed-effects meta-analyses ruled out with high degree of confidence an increase of ≥2% in the risk of CAD among European 719Arg carriers. We also observed no increase in the risk of CAD among 719Arg carriers in the subset of Europeans with early-onset disease (younger than 50 years of age for men and younger than 60 years of age for women) compared with similarly aged controls as well as all non-European subgroups. CONCLUSIONS: The KIF6 Trp719Arg polymorphism was not associated with the risk of clinical CAD in this large replication study.

23 Article Design of the Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) Study: A Genome-wide association meta-analysis involving more than 22 000 cases and 60 000 controls. 2010

Preuss, Michael / König, Inke R / Thompson, John R / Erdmann, Jeanette / Absher, Devin / Assimes, Themistocles L / Blankenberg, Stefan / Boerwinkle, Eric / Chen, Li / Cupples, L Adrienne / Hall, Alistair S / Halperin, Eran / Hengstenberg, Christian / Holm, Hilma / Laaksonen, Reijo / Li, Mingyao / März, Winfried / McPherson, Ruth / Musunuru, Kiran / Nelson, Christopher P / Burnett, Mary Susan / Epstein, Stephen E / O'Donnell, Christopher J / Quertermous, Thomas / Rader, Daniel J / Roberts, Robert / Schillert, Arne / Stefansson, Kari / Stewart, Alexandre F R / Thorleifsson, Gudmar / Voight, Benjamin F / Wells, George A / Ziegler, Andreas / Kathiresan, Sekar / Reilly, Muredach P / Samani, Nilesh J / Schunkert, Heribert / Anonymous91076. ·Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Germany. ·Circ Cardiovasc Genet · Pubmed #20923989.

ABSTRACT: BACKGROUND: Recent genome-wide association studies (GWAS) of myocardial infarction (MI) and other forms of coronary artery disease (CAD) have led to the discovery of at least 13 genetic loci. In addition to the effect size, power to detect associations is largely driven by sample size. Therefore, to maximize the chance of finding novel susceptibility loci for CAD and MI, the Coronary ARtery DIsease Genome-wide Replication And Meta-analysis (CARDIoGRAM) consortium was formed. METHODS AND RESULTS: CARDIoGRAM combines data from all published and several unpublished GWAS in individuals with European ancestry; includes >22 000 cases with CAD, MI, or both and >60 000 controls; and unifies samples from the Atherosclerotic Disease VAscular functioN and genetiC Epidemiology study, CADomics, Cohorts for Heart and Aging Research in Genomic Epidemiology, deCODE, the German Myocardial Infarction Family Studies I, II, and III, Ludwigshafen Risk and Cardiovascular Heath Study/AtheroRemo, MedStar, Myocardial Infarction Genetics Consortium, Ottawa Heart Genomics Study, PennCath, and the Wellcome Trust Case Control Consortium. Genotyping was carried out on Affymetrix or Illumina platforms followed by imputation of genotypes in most studies. On average, 2.2 million single nucleotide polymorphisms were generated per study. The results from each study are combined using meta-analysis. As proof of principle, we meta-analyzed risk variants at 9p21 and found that rs1333049 confers a 29% increase in risk for MI per copy (P=2×10⁻²⁰). CONCLUSION: CARDIoGRAM is poised to contribute to our understanding of the role of common genetic variation on risk for CAD and MI.

24 Article Genetic variants influencing circulating lipid levels and risk of coronary artery disease. 2010

Waterworth, Dawn M / Ricketts, Sally L / Song, Kijoung / Chen, Li / Zhao, Jing Hua / Ripatti, Samuli / Aulchenko, Yurii S / Zhang, Weihua / Yuan, Xin / Lim, Noha / Luan, Jian'an / Ashford, Sofie / Wheeler, Eleanor / Young, Elizabeth H / Hadley, David / Thompson, John R / Braund, Peter S / Johnson, Toby / Struchalin, Maksim / Surakka, Ida / Luben, Robert / Khaw, Kay-Tee / Rodwell, Sheila A / Loos, Ruth J F / Boekholdt, S Matthijs / Inouye, Michael / Deloukas, Panagiotis / Elliott, Paul / Schlessinger, David / Sanna, Serena / Scuteri, Angelo / Jackson, Anne / Mohlke, Karen L / Tuomilehto, Jaako / Roberts, Robert / Stewart, Alexandre / Kesäniemi, Y Antero / Mahley, Robert W / Grundy, Scott M / Anonymous1770673 / McArdle, Wendy / Cardon, Lon / Waeber, Gérard / Vollenweider, Peter / Chambers, John C / Boehnke, Michael / Abecasis, Gonçalo R / Salomaa, Veikko / Järvelin, Marjo-Riitta / Ruokonen, Aimo / Barroso, Inês / Epstein, Stephen E / Hakonarson, Hakon H / Rader, Daniel J / Reilly, Muredach P / Witteman, Jacqueline C M / Hall, Alistair S / Samani, Nilesh J / Strachan, David P / Barter, Philip / van Duijn, Cornelia M / Kooner, Jaspal S / Peltonen, Leena / Wareham, Nicholas J / McPherson, Ruth / Mooser, Vincent / Sandhu, Manjinder S. ·Genetics Division, GlaxoSmithKline R&D, King of Prussia, PA, USA. ·Arterioscler Thromb Vasc Biol · Pubmed #20864672.

ABSTRACT: OBJECTIVE: Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. METHODS AND RESULTS: We combined genome-wide association data from 8 studies, comprising up to 17 723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37 774 participants from 8 populations and also in a population of Indian Asian descent. We also assessed the association between single-nucleotide polymorphisms (SNPs) at lipid loci and risk of CAD in up to 9 633 cases and 38 684 controls. We identified 4 novel genetic loci that showed reproducible associations with lipids (probability values, 1.6×10(-8) to 3.1×10(-10)). These include a potentially functional SNP in the SLC39A8 gene for HDL-C, an SNP near the MYLIP/GMPR and PPP1R3B genes for LDL-C, and at the AFF1 gene for triglycerides. SNPs showing strong statistical association with 1 or more lipid traits at the CELSR2, APOB, APOE-C1-C4-C2 cluster, LPL, ZNF259-APOA5-A4-C3-A1 cluster and TRIB1 loci were also associated with CAD risk (probability values, 1.1×10(-3) to 1.2×10(-9)). CONCLUSIONS: We have identified 4 novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-C, genetic loci mainly associated with circulating triglycerides and HDL-C are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk.

25 Article A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium. 2009

Soranzo, Nicole / Spector, Tim D / Mangino, Massimo / Kühnel, Brigitte / Rendon, Augusto / Teumer, Alexander / Willenborg, Christina / Wright, Benjamin / Chen, Li / Li, Mingyao / Salo, Perttu / Voight, Benjamin F / Burns, Philippa / Laskowski, Roman A / Xue, Yali / Menzel, Stephan / Altshuler, David / Bradley, John R / Bumpstead, Suzannah / Burnett, Mary-Susan / Devaney, Joseph / Döring, Angela / Elosua, Roberto / Epstein, Stephen E / Erber, Wendy / Falchi, Mario / Garner, Stephen F / Ghori, Mohammed J R / Goodall, Alison H / Gwilliam, Rhian / Hakonarson, Hakon H / Hall, Alistair S / Hammond, Naomi / Hengstenberg, Christian / Illig, Thomas / König, Inke R / Knouff, Christopher W / McPherson, Ruth / Melander, Olle / Mooser, Vincent / Nauck, Matthias / Nieminen, Markku S / O'Donnell, Christopher J / Peltonen, Leena / Potter, Simon C / Prokisch, Holger / Rader, Daniel J / Rice, Catherine M / Roberts, Robert / Salomaa, Veikko / Sambrook, Jennifer / Schreiber, Stefan / Schunkert, Heribert / Schwartz, Stephen M / Serbanovic-Canic, Jovana / Sinisalo, Juha / Siscovick, David S / Stark, Klaus / Surakka, Ida / Stephens, Jonathan / Thompson, John R / Völker, Uwe / Völzke, Henry / Watkins, Nicholas A / Wells, George A / Wichmann, H-Erich / Van Heel, David A / Tyler-Smith, Chris / Thein, Swee Lay / Kathiresan, Sekar / Perola, Markus / Reilly, Muredach P / Stewart, Alexandre F R / Erdmann, Jeanette / Samani, Nilesh J / Meisinger, Christa / Greinacher, Andreas / Deloukas, Panos / Ouwehand, Willem H / Gieger, Christian. ·Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK. ns6@sanger.ac.uk ·Nat Genet · Pubmed #19820697.

ABSTRACT: The number and volume of cells in the blood affect a wide range of disorders including cancer and cardiovascular, metabolic, infectious and immune conditions. We consider here the genetic variation in eight clinically relevant hematological parameters, including hemoglobin levels, red and white blood cell counts and platelet counts and volume. We describe common variants within 22 genetic loci reproducibly associated with these hematological parameters in 13,943 samples from six European population-based studies, including 6 associated with red blood cell parameters, 15 associated with platelet parameters and 1 associated with total white blood cell count. We further identified a long-range haplotype at 12q24 associated with coronary artery disease and myocardial infarction in 9,479 cases and 10,527 controls. We show that this haplotype demonstrates extensive disease pleiotropy, as it contains known risk loci for type 1 diabetes, hypertension and celiac disease and has been spread by a selective sweep specific to European and geographically nearby populations.