Abstract 340: The C679X Mutation in PCSK9 is Present and Lowers Blood Cholesterol in a Southern African Population
Missense mutations in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) can cause familial hypercholesterolemia. However, two nonsense variants of PCSK9, Y142X and C679X, found in ~2% of black American subjects, are associated with a 28% reduction in mean low density lipoprotein (LDL)-cholesterol in blood. We sought to determine the frequency and effect of these nonsense variants in an African population. PCSK9 genotypes were determined in 653 black African women attending two antenatal clinics in Zimbabwe. C679X occurred in 3.7% of subjects and was associated with a 27% reduction in LDL-cholesterol (1.6 ± 0.3 mmol/L vs. 2.2 ± 0.7 mmol/L in non-carriers). Of interest, the only C679X homozygous subject found had the lowest LDL-cholesterol out of the 653 subjects, at 0.4 mmol/L. We did not observe the Y142X variant. In summary, our results show that the PCSK9 C679X variant has a marked cholesterol-lowering effect in a population in which the plasma cholesterol concentration is already low, and in homozygous form could be a cause of hypobetalipoproteinemia.