Abstract 9793: Pcsk9 Loss-of-function Variants, Low-density Lipoprotein Cholesterol, and Risk of Coronary Heart Disease and Stroke: Data From the REGARDS Study and CHARGE Consortium

Abstract

Introduction: PCSK9 loss-of-function variants are associated with reduced low-density lipoprotein cholesterol (LDL-C) concentrations. Genetic association studies of PCSK9 loss-of-function variants allow for the examination of the effects of lifetime low LDL-C on cardiovascular outcomes. Hypothesis: PCSK9 loss-of-function variants are associated with lower concentrations of LDL-C and reduced risk of coronary heart disease (CHD) and stroke. Methods: We studied the association of PCSK9 loss-of-function Y142X and C679X nonsense variants (n=366; 2.1%) in 17,459 African Americans (AAs) and R46L missense variants (n=962; 3.1%) in 31,469 whites with LDL-C, CHD and stroke in the US-based REasons for Geographic And Racial Difference in Stroke (REGARDS) study and 8 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We combined multivariable adjusted differences in LDL-C between participants with and without PCSK9 variants across studies using inverse-variance weighted fixed-effects models. We calculated unadjusted odds ratios (ORs) for associations between PCSK9 variants and incident CHD (851 events in AAs and 2,662 events in whites) and stroke (523 events in AAs and 1,660 events in whites) using pooled Mantel-Haenszel estimates with continuity correction factors. Results: In the pooled cohorts, PCSK9 variants were associated with 36 mg/dL (95% confidence interval [CI]: 31, 40) lower LDL-C in AAs and 13 mg/dL (95% CI: 11, 16) lower LDL-C in whites. PCSK9 variants were associated with a pooled OR for CHD of 0.51 (95% CI: 0.28, 0.92) in AAs and 0.82 (95% CI: 0.63, 1.06) in whites. PCSK9 variants were not associated with incident stroke (OR=0.84 [95% CI: 0.48, 1.47] in AAs and OR=1.06 [95% CI: 0.80, 1.41] in whites). Conclusions: These results provide evidence that PCSK9 variants are associated with lifelong reduction in LDL-C and may lead to lower CHD risk, but no effect on stroke risk.