Rare and common variants of APOB and PCSK9 in Korean patients with extremely low low-density lipoprotein-cholesterol levels

Background Screening of variants, related to lipid metabolism in patients with extreme cholesterol levels, is a tool used to identify targets affecting cardiovascular outcomes. The aim of this study was to examine the prevalence and characteristics of rare and common variants of APOB and PCSK9 in Korean patients with extremely low low-density lipoprotein-cholesterol (LDLC) levels. Methods Among 13,545 participants enrolled in a cardiovascular genome cohort, 22 subjects, whose LDL-C levels without lipid-lowering agents were <= 1 percentile (48 mg/dL) of Korean population, were analyzed. Two target genes, APOB and PCSK9, were sequenced by targeted next-generation sequencing. Prediction of functional effects was conducted using SIFT, PolyPhen-2, and Mutation Taster, and matched against a public database of variants. Results Eight rare variants of the two candidate genes (five in APOB and three in PCSK9) were found in nine subjects. Two subjects had more than two different rare variants of either gene (one subject in APOB and another subject in APOB/PCSK9). Conversely, 12 common variants (nine in APOB and three in PCSK9) were discovered in 21 subjects. Among all variants, six in APOB and three in PCSK9 were novel. Several variants previously reported functional, including c. C277T (p. R93C) and c. G2009A (p. G670E) of PCSK9, were found in our population. Conclusions Rare variants of APOB or PCSK9 were identified in nine of the 22 study patients with extremely low LDL-C levels, whereas most of them had common variants of the two genes.The common novelty of variants suggested polymorphism of the two genes among them. Our results provide rare genetic information associated with this lipid phenotype in East Asian people.