Identification of 12 novel loci that confer susceptibility to early-onset dyslipidemia

Abstract

The circulating concentrations of triglycerides, high density lipoprotein (HDL)-cholesterol, and low density lipoprotein (LDL)-cholesterol have a substantial genetic component, and the heritability of early-onset dyslipidemia might be expected to be higher compared with late-onset forms. In the present study, exome-wide association studies (EWASs) were performed for early-onset hypertriglyceridemia, hypo-HDL-cholesterolemia, and hyper-LDL-cholesterolemia, with the aim to identify genetic variants that confer susceptibility to these conditions in the Japanese population. A total of 8,073 individuals aged ≤65 years were enrolled in the study. The EWASs for hypertriglyceridemia (2,664 cases and 5,294 controls), hypo-HDL-cholesterolemia (974 cases and 7,085 controls), and hyper-LDL-cholesterolemia (2,911 cases and 5,111 controls) were performed with Illumina Human Exome-12 v1.2 DNA Analysis BeadChip or Infinium Exome-24 v1.0 BeadChip arrays. The association of allele frequencies for 31,198, 31,133, or 31,175 single nucleotide polymorphisms (SNPs) to hypertriglyceridemia, hypo-HDL-cholesterolemia, or hyper-LDL-cholesterolemia, respectively, was examined with Fisher’s exact test. To compensate for multiple comparisons of genotypes with each of the three conditions, Bonferroni’s correction was applied for statistical significance of association. The results demonstrated that 25, 28 and 65 SNPs were significantly associated with hypertriglyceridemia, hypo-HDL-cholesterolemia and hyper-LDL-cholesterolemia, respectively. Multivariable logistic regression analysis with adjustment for age and sex revealed that all 25, 28 and 65 of these SNPs were significantly associated with hypertriglyceridemia, hypo-HDL-cholesterolemia and hyper-LDL-cholesterolemia, respectively. Following examination of the association of the identified SNPs to serum concentrations of triglycerides, HDL-cholesterol, or LDL-cholesterol, linkage disequilibrium of the SNPs, and results of previous genome-wide association studies, we newly identified chromosomal region 19p12 as a susceptibility locus for hypertriglyceridemia, eight loci (MOB3C-TMOD4, LPGAT1, EHD3, COL6A3, ZNF860-CACNA1D, COL6A5, DCLRE1C, ZNF77) for hypo-HDL-cholesterolemia, and three loci (KIAA0319-FAM65B, UBD, LOC105375015) for hyper-LDL-cholesterolemia. The present study thus identified 12 novel loci that may confer susceptibility to early-onset dyslipidemia. Determination of genotypes for the SNPs at these loci may prove informative for assessment of genetic risk for hypertriglyceridemia, hypo-HDL-cholesterolemia, or hyper-LDL-cholesterolemia in the Japanese population.