Protective lipid-lowering genetic variants in healthy older individuals without coronary heart disease

ABSTRACT Background Disruptive genetic variants in the PCSK9 and APOB genes result in lower serum low-density lipoprotein cholesterol (LDL-C) levels and confer protection against coronary heart disease (CHD). Few studies have measured the prevalence and selective advantage of such variants among healthy older individuals without prior CHD events. Methods and Results We performed targeted sequencing of the PCSK9 and APOB genes in 13,131 healthy older individuals without CHD aged 70 years or older enrolled into the ASPirin in Reducing Events in the Elderly (ASPREE) trial. We detected predicted loss-of-function (pLoF) variants in the PCSK9 and APOB genes, and associated variant carrier status with blood lipid levels. We detected 22 different rare PCSK9/APOB candidate variants with lipid-lowering effect, carried by 104 participants (carrier rate 1 in 126). Rare variant carrier status was associated with 19.4 mg/dl (14.6%) lower LDL-C, compared with non-carriers (P=<0.001, adjusted for statin use). Statin prescriptions were less prevalent in rare variant carriers (16%) than non-carriers (35%). The PCSK9 R46L variant (rs11591147-T) was associated with 15.5mg/dl (11.8%) lower LDL-C in heterozygotes, and 25.2 mg/dl (19.2%) lower LDL-C in homozygotes, respectively (both P=<0.001). Conclusions Lipid-lowering genetic variants are carried by healthy older individuals and contribute to CHD-free survival.