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.
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机译：甘油三酸酯，高密度脂蛋白（HDL）？胆固醇和低密度脂蛋白（LDL）？胆固醇的循环浓度具有重要的遗传成分，与晚发型相比，早发型血脂异常的遗传力可能更高。 。在本研究中，针对早期发作的高甘油三酯血症，低密度脂蛋白胆固醇胆固醇血症和高密度脂蛋白胆固醇胆固醇血症进行了全基因组关联研究（EWAS），目的是确定在日本人中对这些疾病易感的遗传变异。人口。共有8073名年龄≤65岁的人参加了研究。用Illumina Human Exome？12 v1.2 DNA进行高甘油三酯血症（2,664例和5,294例），低HDL-胆固醇血症（974例和7,085例）和高LDL-胆固醇（2,911例和5,111例）的EWAS。分析BeadChip或Infinium Exome？24 v1.0 BeadChip阵列。用Fisher精确检验分别检查了31,198、31,133或31,175个单核苷酸多态性（SNP）的等位基因频率与高甘油三酯血症，低HDL-胆固醇血症或高LDL-胆固醇血症的相关性。为了补偿三种情况下基因型的多重比较，将Bonferroni校正用于关联的统计显着性。结果表明，分别有25、28和65个SNP与高甘油三酯血症，低-HDL-胆固醇血症和高-LDL-胆固醇血症显着相关。经年龄和性别调整的多变量logistic回归分析显示，这些SNP的全部25、28和65分别与高甘油三酯血症，低HDL-胆固醇血症和高LDL-胆固醇血症显着相关。在检查了鉴定出的SNPs与甘油三酸酯，HDL？胆固醇或LDL？胆固醇的血清浓度，SNPs的连锁不平衡以及以前的全基因组关联研究的结果之后，我们新发现了染色体区域19p12作为易感基因座高甘油三酯血症的低位HDL胆固醇血症有8个基因座（MOB3C？TMOD4，LPGAT1，EHD3，COL6A3，ZNF860？CACNA1D，COL6A5，DCLRE1C，ZNF77），三个位点（KIAA0319？FAM65B？胆固醇血症。因此，本研究确定了12个新的基因位点，这些基因位点可导致早期发作的血脂异常。确定这些基因座上SNP的基因型可能为评估日本人群高甘油三酯血症，低密度脂蛋白胆固醇胆固醇血症或高脂蛋白胆固醇胆固醇血症的遗传风险提供了信息。
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