Abstract 1437: The Chromosome 9p21 Risk Locus is Associated with a Greater Severity of Angiographically Defined Coronary Artery Disease
Background: Large-scale genome wide association studies have demonstrated a risk locus at position 9p21 conferring a 1.3–1.5 fold risk of MI and incident CAD in Caucasian populations with an allele frequency of 50%. However, these studies have only associated 9p21 with binary and clinically defined non-angiographic measures of CAD. Definitive demonstration of an association with graded CAD severity would contribute to our understanding of how 9p21 polymorphisms confer risk of MI. We hypothesized that subjects with the 9p21 risk allele would have greater severity of angiographically defined CAD.
Methods: A previously described SNP, rs10757278, at the 9p21 locus was genotyped in 1,341 Caucasian patients from the prospective Emory Genebank Study, using a Centaurus platform (deCODE Genetics). CAD severity was scored by two independent observers based on number of vessels with <50% diameter stenosis (0 = no disease, 1= <50%, 2= 1vd, 3= 2vd and 4= 3vd or more). Ordinal regression analysis (cumulative logit model) was used to examine the association between rs10757278 with severity of CAD. We compared subjects using a dominant model for the risk allele G; AG+GG (n=1033) vs AA (n=308).
Results: We first confirmed the association between rs10757278 and presence of CAD (OR 1.46, 95% CI [1.09–1.94], p=0.009) in our cohort (mean age 64.7, male 68.7%). We then demonstrated a significant association between this SNP and CAD severity. Subjects with the risk allele are 50% more likely to have more severe CAD (one CAD score increment higher) compared to individuals who do not carry the risk allele (OR = 1.51, 95% CI [1.19 –1.92], p = 0.0007). The observed genetic effect on CAD severity was independent of age, gender and traditional cardiovascular risk factors.
Conclusion: In conclusion, we have demonstrated that the 9p21 locus is associated with greater severity of CAD on coronary angiography indicating that this polymorphism may increase the susceptibility to progressive atherosclerosis.