title: The impact of susceptibility loci for coronary artery disease on other vascular domains and recurrence risk.
abstract: OBJECTIVE
  Genome-wide association studies (GWAS) have identified many genetic loci related to coronary artery disease (CAD) and myocardial infarction (MI). However, the extent to which these loci are related to other vascular diseases is not clear. The aim of this study is to investigate the cumulative effects of risk alleles associated with CAD/MI on ischaemic stroke (IS), abdominal aortic aneurysm (AAA), and peripheral artery disease (PAD).
  
  
  RESULTS
  We calculated a multi-locus genetic risk score (GRS) in 8446 participants of the SMART (Second Manifestations of ARTerial disease) study based on the lead single-nucleotide polymorphisms (SNPs) at 30 CAD/MI loci, and tested this GRS for cross-sectional association with CAD/MI, IS, AAA and PAD, adjusting for age and sex. We also investigated whether this GRS was associated with recurrent vascular events using Cox regression, adjusting for age, sex, body mass index, type 2 diabetes, low-density lipoprotein-cholesterol, smoking, and hypertension. We found that the GRS was significantly associated with CAD (P = 1.31 × 10(-9)), IS (P = 0.030), and PAD (P = 6.93 × 10(-04)), but not with AAA (P = 0.057). The lead SNP at the 9p21 locus (rs4977574) was associated with all four vascular diseases (P < 4 × 10(-3)), illustrating the functional pleiotropy of this locus. The GRS was associated with recurrent risk of MI (P = 0.026), with a hazard ratio of 1.13 (95% CI 1.00-1.28) for individuals in the top quartile of the GRS distribution (n = 30 recurrent events) compared with those in the bottom quartile (n = 8 recurrent events). Finally, we found a significant positive relationship between the GRS and the number of vascular events (P = 3.26 × 10(-05)).
  
  
  CONCLUSIONS
  These findings suggest that CAD/MI-associated risk alleles play an aetiological role in different types of atherosclerotic disease.
authors.affiliation: Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Vinicius
authors.initials: V
authors.lastname: Tragante
authors.forename: Pieter A F M
authors.initials: PA
authors.lastname: Doevendans
authors.forename: Hendrik M
authors.initials: HM
authors.lastname: Nathoe
authors.forename: Yolanda
authors.initials: Y
authors.lastname: van der Graaf
authors.forename: Wilko
authors.initials: W
authors.lastname: Spiering
authors.forename: Ale
authors.initials: A
authors.lastname: Algra
authors.forename: Gert Jan
authors.initials: GJ
authors.lastname: de Borst
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.forename: Folkert W
authors.initials: FW
authors.lastname: Asselbergs
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D017544:Aortic Aneurysm, Abdominal / Q000235:genetics; D003324:Coronary Artery Disease / Q000235:genetics*; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics*; D058729:Peripheral Arterial Disease / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012008:Recurrence; D012307:Risk Factors; D020521:Stroke / Q000235:genetics; D055815:Young Adult
keywords: Abdominal aortic aneurysm; Coronary artery disease; Genetic risk score; Ischaemic stroke; Peripheral artery disease; Pleiotropy