Evaluation of polygenic cause in Korean patients with familial hypercholesterolemia - A study supported by Korean Society of Lipidology and Atherosclerosis

•Polygenic cause in Korean patients with FH was evaluated using SNP score analysis.•Weighted mean SNP scores were associated with LDL-C levels in controls.•Mutation-negative FH patients had higher SNP scores than controls.•The utility of SNP score for identifying polygenic FH was newly shown in Asians.

Background/ObjectiveFamilial hypercholesterolemia (FH) is an autosomal dominant disorder caused by mutations in LDLR, APOB, or PCSK9. Polygenicity is a plausible cause in mutation-negative FH patients based on LDL cholesterol (LDL-C)-associated single nucleotide polymorphisms (SNPs) identified by the Global Lipids Genetics Consortium (GLGC). However, there are limited data regarding the polygenic cause of FH in Asians.MethodsWe gathered data from 66 mutation-negative and 31 mutation-positive Korean FH patients, as well as from 2274 controls who participated in the Korean Health Examinee (HEXA) shared control study. We genotyped the patients for six GLGC SNPs and four East Asian LDL-C-associated SNPs and compared SNP scores among patient groups and controls.ResultsWeighted mean 6- and 4-SNP scores (0.67 [SD = 0.07] and 0.46 [0.11], respectively) were both significantly associated with LDL-C levels in controls (p = 2.1 × 10−4, R2 = 0.01 and p = 5.0 × 10−12, R2 = 0.02, respectively). Mutation-negative FH patients had higher 6-SNP (0.72 [0.07]) and 4-SNP (0.49 [0.08]) scores than controls (p = 1.8 × 10−8 and p = 3.6 × 10−3, respectively). We also observed higher scores in mutation-positive FH patients compared with controls, but the difference did not reach statistical significance.ConclusionThe present study demonstrates the utility of SNP score analysis for identifying polygenic FH in Korean patients by showing that small-effect common SNPs may cumulatively elevate LDL-C levels.