Gombojav Bayasgalan, Lee Soo Ji, Kho Minjung, Song Yun-Mi, Lee Kayoung, Sung Joohon
Institute of Health and Environment, Seoul National University, Seoul, Korea Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul, Korea.
Complex Disease and Genome Epidemiology Branch, Department of Epidemiology, School of Public Health, Seoul National University, Seoul, Korea.
J Lipid Res. 2016 Feb;57(2):318-24. doi: 10.1194/jlr.P063461. Epub 2015 Dec 3.
Genetic studies of plasma TG levels have identified associations with multiple candidate loci on chromosome11q23.3, which harbors a number of genes, including BUD13, ZNF259, and APOA5-A4-C3-A1. This study aimed to examine whether these multiple candidate genes on the 11q23.3 regions exert independent effects on TG levels or whether their effects are confounded by linkage disequilibrium (LD). We performed a genome-wide association study and consequent fine-mapping analyses on TG levels in two Korean population-based cohorts: the Korea Association Resource study (n = 8,223) and the Healthy Twin study (n = 1,735). A total of 301 loci reached genome-wide significance level in pooled analysis, including 10 SNPs with weak LD (r(2) < 0.06) clustered on 11q23.3: ApoA5 (rs651821, rs2075291); ZNF259 (rs964184, rs603446); BUD13 (rs11216126); Apoa4 (rs7396851); SIK3 (rs12292858); PCSK7 (rs199890178); PAFAH1B2 (rs12420127), and SIDT2 (rs2269399). When the inter-dependence between alleles was examined using conditional models, five loci on BUD13, ZNF259, and ApoA5 showed possible independent associations. A haplotype analysis using five SNPs revealed both hyper- and hypotriglyceridemic haplotypes, which are relatively common in Koreans (haplotype frequency 0.08-0.22). Our findings suggest the presence of multiple functional loci on 11q23.3, which might exert their effects on plasma TG level independently or through complex interactions between functional loci.
血浆甘油三酯（TG）水平的遗传学研究已确定其与11号染色体q23.3区域的多个候选基因座相关，该区域包含许多基因，包括BUD13、ZNF259和APOA5 - A4 - C3 - A1。本研究旨在检验11q23.3区域的这些多个候选基因是否对TG水平发挥独立作用，或者它们的作用是否受到连锁不平衡（LD）的混淆。我们对两个基于韩国人群的队列（韩国协会资源研究，n = 8223；健康双胞胎研究，n = 1735）的TG水平进行了全基因组关联研究及后续的精细定位分析。在汇总分析中，共有301个基因座达到全基因组显著性水平，其中包括10个处于弱LD（r² < 0.06）状态且聚集在11q23.3区域的单核苷酸多态性（SNP）：载脂蛋白A5（rs651821、rs2075291）；锌指蛋白259（rs964184、rs603446）；BUD13（rs11216126）；载脂蛋白A4（rs7396851）；盐诱导激酶3（rs12292858）；前蛋白转化酶枯草溶菌素9（PCSK7，rs199890178）；血小板活化因子乙酰水解酶1b2（PAFAH1B2，rs12420127）以及溶质载体家族29成员2（SIDT2，rs2269399）。当使用条件模型检验等位基因之间的相互依赖性时，BUD13、ZNF259和载脂蛋白A5上的五个基因座显示出可能的独立关联。使用五个SNP进行的单倍型分析揭示了高甘油三酯血症和低甘油三酯血症单倍型，这些单倍型在韩国人中相对常见（单倍型频率为0.08 - 0.22）。我们的研究结果表明11q23.3区域存在多个功能基因座，它们可能独立地或通过功能基因座之间的复杂相互作用对血浆TG水平产生影响。
