Abstract 17297: 9p21 CAD Risk Allele is Protective Against Calcific Aortic Stenosis

Abstract

The 9p21 locus has emerged as one of the strongest risk variants associated with coronary artery disease (CAD). The risk allele for CAD is also associated with other vascular pathologies, including abdominal aortic aneurysms and intracranial aneurysms. Calcific aortic stenosis (AS) and CAD share some risk factors and histopathologic features. However, a considerable proportion of severe AS patients have no significant CAD, indicating the presence of unique mechanisms underlying each condition. To date only one common genetic variant, rs10455872 in the LPA gene, has been robustly associated with risk of AS. Here we investigated the association of the lead CAD-associated variant (rs1333049) at the 9p21 locus with the risk of AS in 1044 cases and 4527 controls. We also typed the LPA SNP (rs10455872) as a validated variant. All cases had either echo confirmed AS of abnormal valve morphology and peak velocity across the aortic valve of more than 2.5 meters/second, or they had previously undergone surgery for severe AS. We used logistic regression analysis to investigate the additive effect of both variants on risk of AS, adjusting for CAD status. For the LPA locus, we observed the previously reported association of the G allele at rs10455872 with risk of AS (OR 1.23; 95% CI, 1.06 to 1.44, P= 0.008). Interestingly for the 9p21 locus, the CAD associated allele (C) for rs1333049 was associated with a lower risk of AS (OR 0.88; 95% CI, 0.80 to 0.98, P= 0.014). In an additional analysis, we examined the association of rs1333049 with AS in our 1044 cases against an independent set of 828 controls with no history of AS, and the results were consistent with the initial findings (OR 0.76; 95% CI, 0.66 to 0.87, P= 0.0001). This unexpected finding requires further validation, but suggests that the 9p21 locus CAD-associated variant is not uniformly deleterious for other vascular pathologies - and for AS may be protective. If the 9p21 finding is confirmed, then understanding the differential effect of this locus on AS and CAD may help to better understand the specific pathogenesis of each condition.