Abstract 37: A Multi-locus Genetic Risk Score for Abdominal Aortic Aneurysm

Abstract

Background: Genome-wide association studies (GWAS) have identified several common variants associated with abdominal aortic aneurysm (AAA). We investigated whether a multi-locus genetic risk score (GRS) for AAA was associated with presence and progression of AAA in a case-control study. Methods: The study comprised of 1098 patients with AAA (74±8 years, 83% men) and 6538 controls (67±10 years, 58% men) enrolled in the Mayo Vascular Disease Biorepository. AAA was defined as a transverse diameter of abdominal aorta ≥ 3.0 cm or history of AAA repair. Controls were participants without known AAA. We found five single nucleotide polymorphisms (SNPs) previously shown to be associated with AAA at GWAS significance (P≤10^-8) in NHGRI GWAS catalog and PubMed. A GRS for AAA for each individual was calculated from four SNPs (rs2383107, rs7025486, rs599839, rs1466535) that were replicated in our cohort, by summing the number of risk alleles for each SNP weighted by their estimated effect sizes in GWAS catalog or published largest meta-analysis. Results: GRS was associated with presence of AAA: odds ratio (OR) (95% confidence interval): 1.06 (1.03-1.08). The association remained significant after adjustment for age, sex, cardiovascular risk factors, and atherosclerotic cardiovascular diseases: adjusted OR: 1.05 (1.03-1.08). Further adjustment for each SNP did not attenuate association of GRS with presence of AAA (All P<0.001). GRS was not associated with family history of aortic aneurysm (P=0.4). Adding GRS to conventional risk factors improved net reclassification index by 16% (P<0.001).In a subset of patients with AAA who had sequential imaging studies (n=628), GRS was associated with AAA growth rate ≥ 1.75 mm/year (median of the cohort) after adjustment for baseline AAA size: adjusted OR: 1.07 (1.00-1.14). No conventional risk factors were associated with AAA growth. Patients with GRS > 5.24 (median of the cohort) had 1.31 times higher odds of having AAA and 1.64 times higher odds of having AAA growth rate ≥1.75 mm/year compared to those with GRS ≤ 5.24 (both P≤0.005). Conclusions: A multi-locus GRS was associated with presence of AAA and aneurysm growth, suggesting genetic predisposition to disease initiation and progression.