PCSK9 R46L loss-of-function mutation reduces lipoprotein(a), LDL cholesterol, and risk of aortic valve stenosis

Abstract

Context: Novel, low-density lipoprotein (LDL) cholesterol-lowering proprotein convertase subtil-isin/kexin type-9 (PCSK9) inhibitors also lower lipoprotein(a) levels, but the effect on aortic valve stenosis and myocardial infarction is unknown. Objective: We tested the hypothesis that the PCSK9 R46L loss-of-function mutation is associated with lower levels of lipoprotein(a) and with reduced risk of aortic valve stenosis and myocardial infarction. Design: We used two prospective cohort studies of the general population and one patient-based cohort. Setting: Cohort studies selected at random individuals of Danish descent. Participants: We studied 103 083 individuals from the Copenhagen General Population Study, the Copenhagen City Heart Study, and the Copenhagen Ischemic Heart Disease Study. Main outcome measures: Lipoprotein(a), LDL cholesterol, and PCSK9 R46L genotype and diagnoses of aortic valve stenosis and myocardial infarction from national registries; lipoprotein(a) was measured from 49,617 individuals. Results: Median (interquartile range) lipoprotein(a) levels were 10 (5-30) mg/dl for PCSK9 R46L noncarriers, 9 (4-32) mg/dl for heterozygotes, and 8 (4-42) mg/dl for homozygotes (trend P = .02). The corresponding values for LDL cholesterol levels were 124 (101-147) mg/dl, 104 (85-132) mg/dl, and 97 (85-128) mg/dl, respectively (trend P = 2 × 10-52). PCSK9 R46L carriers vs noncarriers had an age- and sex-adjusted odds ratio of 0.64 (95% confidence interval, 0.44-0.95) for aortic valve stenosis, 0.77 (0.65-0.92) for myocardial infarction, and 0.76 (0.64-0.89) for aortic valve stenosis or myocardial infarction. Conclusions: PCSK9 R46L carriers have lower levels of lipoprotein(a) and LDL cholesterol as well as reduced risk of aorticvalve stenosis and myocardial infarction. This indirectly suggests that PCSK9 inhibitors may have a role in patients with aortic valve stenosis.