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PLoS One. 2016 Mar 7;11(3):e0144997. doi: 10.1371/journal.pone.0144997. eCollection 2016.

Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium.

Author information

  • 1Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • 2Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
  • 3Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States of America.
  • 4Icelandic Heart Association, Kopavogur, Iceland.
  • 5University of Iceland, Reykjavik, Iceland.
  • 6Human Genetics Center, and Division of Epidemiology, Human Genetics, and Environmental Sciences, University of Texas Health Science Center at Houston, Houston, TX, United States of America.
  • 7Boston University's and National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA, United States of America.
  • 8Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
  • 9Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
  • 10Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
  • 11Department of Biostatistics, University of Washington, Seattle, WA, United States of America.
  • 12Department of Statistics, University of Auckland, Auckland, New Zealand.
  • 13Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
  • 14DZHK (German Center for Cardiovascular Research), partner site, Greifswald, Germany.
  • 15Department of Pharmacology and Therapeutics, University College, Cork, Ireland.
  • 16Department of Internal Medicine, Division of Geriatrics, Wake Forest University, Winston-Salem, North Carolina, United States of America.
  • 17Department of Nutrition, Harvard School of Public Health, Boston, MA, United States of America.
  • 18Channing Division of Network Medicine, Harvard Medical School, Boston, MA, United States of America.
  • 19Division of Epidemiology & Community Health, School of Public Health, University of Minnesota, Minneapolis, United States of America.
  • 20Sticht Center on Aging, Wake Forest School of Medicine, Winston-Salem, NC, United States of America.
  • 21Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, United States of America.
  • 22Department of Epidemiology, Merck Research Laboratories, Merck Sharp & Dohme Corp., Whitehouse Station, NJ, United States of America.
  • 23Robertson Centre for Biostatistics, University of Glasgow, Glasgow, United Kingdom.
  • 24Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.
  • 25National Institute for Health and Welfare, Helsinki, Finland.
  • 26Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • 27Department of Epidemiology, Boston University School of Public Health, Boston, MA, United States of America.
  • 28Department of Medicine, Boston University School of Medicine, Boston, MA, United States of America.
  • 29Department of Preventive Medicine, Boston University School of Medicine, Boston, MA, United States of America.
  • 30Section of Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, United States of America.
  • 31Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America.
  • 32Department of Epidemiology and Public Health, Pasteur Institute of Lille, Lille, France.
  • 33Department of Epidemiology and Public Health, EA 3430, University of Strasbourg, Strasbourg, France.
  • 34Department of Epidemiology, University of Washington, Seattle, WA, United States of America.
  • 35Group Health Research Institute, Group Health Cooperative, Seattle, United States of America.
  • 36Departments of Cardiology and Epidemiology, Toulouse University Hospital, Toulouse, France.
  • 37National Institute of Health and Medical Research (U258), Paris, France.
  • 38Seattle Epidemiologic Research and Information Center of the Department of Veterans Affairs Office of Research and Development, Seattle, WA, United States of America.
  • 39Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA, United States of America.
  • 40The New York Academy of Medicine, New York, NY, United States of America.
  • 41Department of Medicine, Umeå University Hospital, Umeå, Sweden.
  • 42Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Torrance, CA, United States of America.
  • 43Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, United States of America.
  • 44UKCRC Centre of Excellence for Public Health Research (Northern Ireland), Queen's University of Belfast, Belfast, United Kingdom.
  • 45Department of Mathematics and Statistics, University of Jyväskylä, Jyväskylä, Finland.
  • 46Department of Epidemiology, Harvard School of Public Health, Boston, MA, United States of America.
  • 47Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States of America.
  • 48Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
  • 49Institute for Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland.
  • 50Department of Epidemiology & Prevention, Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, 27157, United States of America.
  • 51Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom.
  • 52Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands.
  • 53Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands.
  • 54Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
  • 55Department of General and Interventional Cardiology, University Heart Center Hamburg-Eppendorf, Hamburg, Germany.
  • 56Department of Health Services, University of Washington, Seattle, WA, United States of America.
  • 57Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America.
  • 58Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD, United States of America.
  • 59Cardiology Section, Department of Medicine, Boston Veteran's Administration Healthcare, Boston, MA, United States of America.

Abstract

BACKGROUND:

Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting.

METHODS:

We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up.

RESULTS:

In Stage I 15 loci passed the threshold of 5×10-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10-3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10-9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10-3).

CONCLUSIONS:

QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.

PMID:
26950853
[PubMed - in process]
PMCID:
PMC4780701
Free PMC Article
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