Ye, Zi

Introduction: Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death worldwide. The genetic contribution to mortality in patients with ASCVD is unknown. Hypothesis: Abdominal aortic aneurysm (AAA) often co-exists with ASCVD and two with shared genetic susceptibility underlying disease development. We hypothesiz that a genetic risk score (GRS) for susceptibility variants to AAA and ASCVD increases the risk for all-cause mortality in patients with ASCVD. Methods: We analyzed high-density genotyping data in 3053 participants (age 71 ±10 years, 72% men) with ASCVD in Mayo Vascular Disease Biorepository. We used 4 single nucleotide polymorphisms (SNPs) (rs2383207, rs7025486, rs599839, rs1466535) previously shown to be associated with AAA and ASCVD at GWAS significance (P ≤10^-8) in the NHGRI GWAS catalog to build the GRS. We defined ASCVD as a history of myocardial infarction / coronary revascularization / ischemic stroke / peripheral arterial disease with revascularization. Results: Patients with GRS > median level had similar age (70±10 vs. 71±10), prevalence of men (72% vs. 73%), hypertension (83% vs. 82%), diabetes (32% vs. 31%) and smokers (74% vs. 72%) compared to those with GRS ≤ median (all P>0.2), except for dyslipidemia (91% vs. 88%, P =0.02). After a median follow-up of 4.56 years (interquartile: 3.07-6.26), 620 patients died. Patients with GRS > median had poorer survival compared to those with GRS ≤ median (Figure: Kaplan-Meier curve); and with 23% higher risk for death after adjustment for age, sex and cardiovascular risk factors (hazard ratio HR, 95% CI: 1.23, 1.05-1.45). The association of GRS with all-cause mortality remained significant after excluding patients with known AAA (n=672) (HR, 95%CI: 1.22, 1.01-1.48). Conclusions: A GRS for susceptibility variants of AAA and ASCVD is a prognostic marker in patients with ASCVD.