title: Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium.
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.
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
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authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States of America.
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authors.affiliation: Icelandic Heart Association, Kopavogur, Iceland.|University of Iceland, Reykjavik, Iceland.
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authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
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authors.affiliation: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America.|Department of Epidemiology, University of Washington, Seattle, WA, United States of America.|Group Health Research Institute, Group Health Cooperative, Seattle, United States of America.|Department of Health Services, University of Washington, Seattle, WA, United States of America.
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authors.affiliation: Human 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.|Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America.
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authors.affiliation: Boston University's and National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA, United States of America.|Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD, United States of America.|Cardiology Section, Department of Medicine, Boston Veteran's Administration Healthcare, Boston, MA, United States of America.
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mesh_terms: D000368:Aged; D015331:Cohort Studies; D003299:Cooperative Behavior; D003324:Coronary Artery Disease / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000453:epidemiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies