The effect of CAD/MI SNPs on other vascular domains and the relation with recurrent vascular events. V. Tragante1,2, P. A. F. M. Doevendans1, H. M. Nathoe1, Y. van der Graaf3, W. Spiering4, A. Algra3,5, G. J. de Borst6, P. I. W. de Bakker2,3,7,8, F. W. Asselbergs1,3,9 1) Division Heart & Lungs, University Medical Center Utrecht, Utrecht, Netherlands; 2) Division Biomedical Genetics, University Medical Center Utrecht, Utrecht, Netherlands; 3) Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, The Netherlands; 4) Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands; 5) Department of Neurology, Rudolph Magnus Institute for Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands; 6) Vascular Surgery, UMC University Medical Center Utrecht, Utrecht, The Netherlands; 7) Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachussetts; 8) Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts; 9) Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands.

   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. 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 SNPs at 30 CAD/MI loci, and tested this GRS for cross-sectional association to CAD/MI, ischemic stroke (IS), abdominal aortic aneurysm (AAA) and peripheral artery disease (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, BMI, type 2 diabetes, LDL cholesterol, smoking and hypertension. We found that the GRS was significantly associated with CAD (p=1.31 x 10-9), IS (p=0.030) and PAD (p=6.93 x 10-04), but not with AAA (p=0.057). The lead SNP at the 9p21 locus (rs4977574) was associated with all 4 vascular diseases (p < 4 x 10-3), illustrating the functional pleiotropy of this locus. We observed a nominally significant association for rs964184 (gene complex APOA5-A4-C3-A1 on chromosome 11) where the T allele confers increased risk for IS (OR = 1.32 (95% CI 1.14 - 1.52, p = 2.33 x 10-04)). The GRS was associated with recurrent risk of MI (p=0.026), with a HR of 1.13 (95% CI 1.00 - 1.28) for individuals in the top quartile of the GRS distribution (N=30 recurrent events) compared to 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 x 10-05). These findings suggest that CAD/MI associated risk alleles play an etiological role in different types of atherosclerotic disease.

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