Abstract 3453: PCSK9 R46L Heterozygosity, Lifelong Low LDL Cholesterol Levels, and Disproportionately Lower Risk of Ischemic Heart Disease: Three Independent Studies and Meta-Analyses
PCSK9 R46L has been associated with low LDL cholesterol levels, and decreased risk of ischemic heart disease (IHD), but results differ between studies. We tested the hypothesis that R46L predicts risk of IHD and longevity in three studies comprising a total of 6,678 cases and 36,869 controls. We genotyped individuals in the Copenhagen City Heart Study (CCHS; N=10,032), the Copenhagen General Population Study (CGPS; N=26,013), and the Copenha-gen Ischemic Heart Disease Study (CIHDS; N=7,502) for PCSK9 R46L and performed meta-analyses of present and previous studies combined. R46L associated with lifelong reductions in LDL cholesterol of 0.35– 0.55 mmol/L (11–16%) in all three studies in heterozygotes (2.6%) versus non-carriers (p-values<0.0001). Multifactorially adjusted hazard/ odds ratios for IHD for R46L heterozygotes versus non-carriers were 0.94 (95%CI: 0.68 –1.31) in the prospective CCHS, 0.54 (0.39 – 0.77) in the cross-sectional CGPS, and 0.82 (0.55–1.21) in the CIHDS case-control study. In all three studies combined, the corresponding multifacto-rially adjusted odds ratio was 0.70 (0.58 – 0.86). In the CCHS, hazard ratio for longevity in heterozygotes versus non-carriers was 1.18 (0.93–1.50). In meta-analyses of present and previous studies (60,834 and 64,546 individuals), R46L heterozygotes had 0.43 mmol/L (12%) lower LDL cholesterol levels than non-carriers, and an odds ratio for IHD of 0.72 (0.62– 0.84), similar to results in our three studies combined. However, the observed 0.43 mmol/L lower LDL cholesterol levels theoretically predicted an odds ratio for IHD of only 0.95 (0.92– 0.97). In conclusion, R46L heterozygosity is associated with life-long 13% lower LDL cholesterol levels, and a disproportionate 30% lower risk of IHD compared with the 5% predicted by the reduction in LDL cholesterol alone. These results suggest that PCSK9 may have direct atherogenic effects that are independent of plasma levels of LDL cholesterol.