期刊
STROKE
卷 45, 期 1, 页码 24-36出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/STROKEAHA.113.002707
关键词
coronary artery disease; genetics; meta-analysis; polymorphism; single nucleotide; stroke
资金
- University of Newcastle
- Australian National Health and Medical Research Council (NHMRC) [569257]
- Australian National Heart Foundation (NHF) [G 04S 1623]
- Gladys M Brawn Fellowship scheme
- Vincent Fairfax Family Foundation in Australia
- National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN26820110 0008C, HHSN268201100009C, HHSN268201100010C, HHSN268 201100011C, HHSN268201100012C, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, N01-HC-85239, HL080295, HL087652, HL105756, R01 HL085251, R01 HL073410, HL087647, R01HL089650-02]
- National Human Genome Research Institute [U01HG004402]
- National Institutes of Health (NIH) [HHSN268200625226C]
- METASTROKE project [HL-093029]
- Senior Fellowship from the Department of Health (United Kingdom)
- National Institute on Aging [AG-023629, AG-15928, AG-20098, AG-027058]
- National Center for Research Resources [UL1RR033176, U54 RR020278]
- National Center for Advancing Translational Sciences, Clinical and Translational Science Institute [UL1TR000124]
- National Institute of Diabetes and Digestive and Kidney Disease [DK063491]
- European Community [HEALTH-F4-2007]
- FHS
- National Heart, Lung, and Blood Institute's FHS [N01-HC-25195, N02-HL-6-4278]
- National Institute of Neurological Disorders and Stroke [NS17950]
- National Heart, Lung, and Blood Association [HL93029]
- National Institute of Aging [AG033193]
- NIH Genes, Environment and Health Initiative (GEI), as part of the GENEVA consortium under the NIH Genes, Environment, and Health Initiative [U01 HG004436]
- Mid-Atlantic Nutrition, and Obesity Research Center [P30 DK072488]
- Office of Research and Development
- Medical Research Service
- Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs
- NIH [HHSN268200782096C, Z01 AG-000015-50, N01-AG-12100, P01 HL098055, P01HL076491-06, R01DK080732, P01HL087018, 1RO1HL103931-01]
- Division of Adult and Community Health
- Centers for Disease Control
- National Institute of Neurological Disorders and Stroke
- NIH Office of Research on Women's Health [R01 NS45012, U01 NS069208-01]
- UK Medical Research Council
- British Heart Foundation (BHF)
- Merck & Co (manufacturers of simvastatin)
- Roche Vitamins Ltd
- Merck Co.
- BHF Centre of Research Excellence, Oxford [RE/08/004]
- Intramural Research Program of the National Institute on Aging, NIH project [Z01 AG-000954-06]
- NIH-National Institute of Neurological Disorders and Stroke [R01 NS-42733, R01 NS-39987, U01 NS069208]
- American Heart Association/Bugher Foundation Centers for Stroke Prevention Research [0775010 N]
- National Heart, Lung, and Blood Institute's SNP Typing for Association with Multiple Phenotypes from Existing Epidemiologic Data (STAMPEED) genomics research program [R01 HL087676]
- National Center for Research Resources
- Annual Research Funding of the Italian Ministry of Health [RC 2007/LR6, RC 2008/LR6, RC 2009/LR8, RC 2010/LR8]
- Netherlands Organization of Scientific Research [175.010.2005.011]
- Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) Netherlands Consortium for Healthy Ageing [050-060-810]
- Erasmus Medical Center and Erasmus University, Rotterdam
- Netherlands Organization for Health Research and Development
- Research Institute for Diseases in the Elderly
- Ministry of Education, Culture, and Science
- Ministry for Health, Welfare, and Sports
- European Commission
- Municipality of Rotterdam to the Rotterdam Study
- Netherlands Heart Foundation (Nederlandse Hartstichting) [2009B102]
- Wellcome Trust, as part of the WTCCC2 project [085475/B/08/Z, 085475/Z/08/Z, WT084724MA]
- Medical Research Council
- Stroke Association
- Dunhill Medical Trust
- National Institute of Health Research (NIHR)
- NIHR Biomedical Research Centre, Oxford
- Scottish Funding Council
- Chief Scientist Office
- Vascular Dementia Research Foundation
- BHF Center of Research Excellence in Oxford
- Wellcome Trust [090532/Z/09/Z, 075491/Z/04, 084723/Z/08/Z]
- Reynold's Foundation
- Boehringer Ingelheim
- PHILIPS medical Systems
- Government of Rheinland-Pfalz in the context of the Stiftung Rheinland-Pfalz fur Innovation
- research program Wissenschaft Zukunft
- Johannes-Gutenberg University of Mainz in the context of the Schwerpunkt Vaskulare Pravention
- MAIFOR
- Fondation de France
- French Ministry of Research
- Institut National de la Sante et de la Recherche Medicale
- Deutsche Forschungsgemeinschaft
- German National Genome Research Network (NGFN-2)
- German National Genome Research Network (NGFN-plus)
- EU [LSHM-CT-2006-037593, LSHM-CT-2004-503485, HEALTHF2-2008-201668]
- US NIH
- National Heart, Lung, and Blood Institute's STAMPEED genomics research program [R01 HL087676]
- Canada Graduate Doctoral Scholarship from the Canadian Institutes of Health Research
- Cardiovascular Institute of the University of Pennsylvania
- MedStar Research Institute
- Washington Hospital Center
- GlaxoSmithKline
- GlaxoSmithKline through an Alternate Drug Discovery Initiative research alliance award
- University of Pennsylvania School of Medicine
- Canadian Institutes of Health Research [MOP-82810, MOP172605, MOP77682]
- Canada Foundation for Innovation [11966]
- Heart and Stroke Foundation of Ontario [NA6001]
- BHF
- Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease
- National Institute on Aging Intramural Research Program
- Hjartavernd (the Icelandic Heart Association)
- Althingi (the Icelandic Parliament)
- German Migraine & Headache Society (DMKG)
- Astra Zeneca
- Berlin Chemie
- Boots Healthcare
- Glaxo-Smith-Kline
- McNeil Pharma
- MSD Sharp Dohme
- Pfizer
- Institute of Epidemiology and Social Medicine, University of Muenster
- Medical Research Council (United Kingdom)
- Cancer Research UK
- Canadian Institutes of Health Research, Heart, and Stroke Foundation of Ontario
- Sanofi-Aventis
- King Pharmaceuticals
- LEEDS
- Erasmus Medical Center and Erasmus University Rotterdam
- Netherlands Organization for Scientific Research
- Netherlands Organization for Health Research and Development (ZonMw)
- Netherlands Heart Foundation
- Ministry of Education, Culture and Science
- Ministry of Health Welfare and Sports
- European Commission (DG XII)
- Municipality of Rotterdam
- Netherlands Organization for Scientific Research [175.010.2005.011, 911.03.012]
- NGI/NWO [050-060-810]
- Research Institute for Diseases in the Elderly (RIDE)
- NWO (Vici) [918-76-619]
- Swedish Research Council
- Swedish Heart & Lung Foundation
- Stockholm County Council (ALF)
- Netherlands Heart foundation [NHS 92345]
- Netherlands Organisation for Scientific Research (NWO)
- Italian Ministry of University and Research
- Veneto Region
- Cariverona Foundation, Verona
- Helmholtz Zentrum Munchen-National Research Center for Environmental Health
- German Federal Ministry of Education, Science, Research and Technology
- State of Bavaria
- Munich Center of Health Sciences (MC Health) as part of LMUinnovativ
- Leicester NIHR Biomedical Research Unit in Cardiovascular Disease
- NIHR
- European Community Sixth Framework Program [LSHM-CT-2007-037273]
- AstraZeneca
- Oxford BHF Centre of Research Excellence
- Knut and Alice Wallenberg Foundation
- Swedish Heart-Lung Foundation
- Torsten and Ragnar Soderberg Foundation
- Strategic Cardiovascular Program of Karolinska Institutet and Stockholm County Council
- Foundation for Strategic Research
- Stockholm County Council [560283]
- National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust
- National Institute for Health Research Cardiovascular Biomedical Research Unit of Royal Brompton
- Harefield NHS Foundation Trust
- BHF [SP/04/002]
- Medical Research Council [G0601966, G0700931]
- NIHR [RP-PG-0407-10371]
- European Union FP7 (EpiMigrant) [279143]
- Action on Hearing Loss [G51]
- [R01HL087641]
- [R01H L59367]
- [R01HL086694]
- [R01-HL087641]
- [U01 HL096917]
- [R01-HL093029]
- [UL1RR025005]
- [HHSN268201200036C]
- MRC [G0601966, MC_U137686857, G0700931] Funding Source: UKRI
- Medical Research Council [G0601966, G0700931, MC_U137686857] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0508-10266] Funding Source: researchfish
Background and Purpose Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases. Methods Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genome-wide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance (P<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2167 individuals with the ischemic large artery stroke (LAS) subtype. Results Common variants associated with CAD at P<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, 3 and 5 loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (P<5x10(-8)) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Because these loci had prior evidence for genome-wide significance for CAD, we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (P-IS=1.62x10(-7)) and ABO (P-IS=2.6x10(-4)), as well as at HDAC9 (P-LAS=2.32x10(-12)), 9p21 (P-LAS=3.70x10(-6)), RAI1-PEMT-RASD1 (P-LAS=2.69x10(-5)), EDNRA (P-LAS=7.29x10(-4)), and CYP17A1-CNNM2-NT5C2 (P-LAS=4.9x10(-4)). Conclusions Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.
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