A Multi-locus Genetic Risk Score for Abdominal Aortic Aneurysm

Background: Abdominal aortic aneurysm (AAA) is a complex trait with an important genetic component in disease development. Early detection followed by elective AAA repair remains the mainstream of therapy. Several genetic susceptibility loci for AAA have been identified by genome-wide association studies (GWAS). The prevalence of AAA is higher in patients with atherosclerotic cardiovascular disease (ASCVD) than that in the general population. Genetic variants in known loci for AAA are either associated with ASCVD or risk factors for ASCVD (such as lipid traits) suggesting shared genetic background between two phenotypes. Sex differences in disease presentation and progression are implicated in AAA in both clinical and animal studies. We aimed to assess whether 1) a genetic risk score (GRS) for AAA can improve disease identification beyond conventional risk factors and is associated with aneurysm expansion; 2) a GRS derived from pleiotropic loci for AAA and ASCVD predicts survival in patients with AAA and ASCVD respectively; 3) whether genetic variants are differentially associated with aneurysm expansion in women and men.;Methods: We utilized high-density genotyping information available in patients from Mayo Vascular Biorepository (n=8062). We identified 1124 with AAA (113 women/538 men included in the analysis for aneurysm progression with ≥ 2 measures of AAA size with time interval ≥ 3 months) vs 6524 without known AAA (70% with ASCVD and 30% without any vascular disease).;Results: GRS was associated with presence of AAA independent of age, sex, BMI, hypertension, diabetes, smoking, dyslipidemia, ASCVD and family history: adjusted OR 1.06 (95% CI: 1.04-1.09, p<0.001). Adding GRS to conventional risk factors increased c-statistics from 0.788 (95%CI: 0.776-0.802) to 0.791 (95% CI: 0.777-0.803, p=0.049 for c-statistic increase), net reclassification index 0.14 (p<0.001). The mean (SE) baseline AAA size was 3.69 (0.03) cm and mean (SE) growth rate was 2.47(0.11) mm/year. The mean time interval between two measures was 5.41+/-3.56 years. GRS (dichotomized by median), baseline aneurysm size, diabetes and family history were associated with aneurysm growth rate in univariate analysis. The estimated mean aneurysm growth rate was 0.50 mm/year greater in patients with GRS > median than those with GRS ≤ median after adjustment for covariates. Stepwise linear regression analyses revealed common (age, baseline size) and unique risk factors for aneurysm expansion in women (mean BP) and men (body-mass index and pulse pressure), and sex difference in effect size of susceptibility variants (DAB2IP and SORT1) for AAA.;Conclusions: A multi-locus GRS for AAA can improve disease discrimination for AAA beyond conventional risk factors and is associated with aneurysm expansion. Mean BP, PP and DAB2IP genotype influence aneurysm expansion more prominently in women than men. Such a GRS of pleiotropic loci for AAA and ASCVD can predict survival in patients with AAA and ASCVD. (Abstract shortened by ProQuest.).