Variation in PCSK9, low LDL cholesterol, and risk of peripheral arterial disease

Background: We hypothesized that variants in PCSK9 that lower LDL cholesterol levels are associated with reduced prevalence and incidence of peripheral artery disease (PAD). Methods: The Atherosclerosis Risk in Communities (ARIC) Study assessed risk factors and PCSK9 variants Y142X and C679X (relevant to blacks) and R46L (relevant to whites) in a cohort of 45-64-year olds in 1987-1989 (n = 13,634). Prevalent PAD (n = 619 cases) was defined by an ankle-brachial index <0.9 or a history of leg claudication. Incident PAD (n = 895) was identified from 1987 to 1998 by the same PAD criteria or a PAD hospitalization. Results: As expected, greater LDL cholesterol was a risk factor for prevalent and incident PAD. 2.4% of blacks and 3.1% of whites were carriers of one of the race-specific PCSK9 variants. Carriers had lower prevalence of PAD compared with non-carriers (2.3% vs. 4.6%). The corresponding age- and sex-adjusted odds ratio of PAD was 0.47 (95% confidence interval, 0.24-0.92). In contrast with the cross-sectional findings, there was no association between PCSK9 variants and incident PAD (age- and sex-adjusted hazard ratio, 1.09 (95% confidence interval, 0.76-1.57)). Conclusions: Our study provides mixed evidence that variation in PCSK9 may contribute to genetic risk of PAD.