Genetic Variants at Newly Identified Lipid Loci Are Associated with Coronary Heart Disease in a Chinese Han Population

BackgroundRecent genome-wide association studies (GWAS) have mapped several novel loci influencing blood lipid levels in Caucasians. We sought to explore whether the genetic variants at newly identified lipid-associated loci were associated with CHD susceptibility in a Chinese Han population. Methodology/Principal FindingsWe conducted a two-stage case-control study in a Chinese Han population. The first-stage, consisting of 1,376 CHD cases and 1,376 sex and age- frequency matched controls, examined 5 novel lipid-associated single-nucleotide polymorphisms (SNPs) identified from GWAS among Caucasians in relation to CHD risk in Chinese. We then validated significant SNPs in the second-stage, consisting of 1,269 cases and 2,745 controls. We also tested associations between SNPs within the five novel loci and blood lipid levels in 4,121 controls. We identified two novel SNPs (rs599839 in CELSR2-PSRC1-SORT1 and rs16996148 in NCAN-CILP2) that were significantly associated with reduced CHD risk in Chinese (odds ratios (95% confidence intervals) in the dominant model 0.76 (0.61-0.90; P = 0.001), 0.67 (0.57-0.77; P = 3.4×10−8), respectively). Multiple linear regression analyses using dominant model showed that rs599839 was significantly associated with decreased LDL levels (P = 0.022) and rs16996148 was significantly associated with increased LDL and HDL levels (P = 2.9×10−4 and 0.001, respectively). Conclusions/SignificanceWe identified two novel SNPs (rs599839 and rs16996148) at newly identified lipid-associated loci that were significantly associated with CHD susceptibility in a Chinese Han population.背景 近期的全基因组关联研究（Genome-Wide Association Study, GWAS）已在高加索人群中定位到多个影响血脂水平的全新基因座。本研究旨在探究新发现的血脂相关基因座上的遗传变异，在中国汉族人群中是否与冠心病（Coronary Heart Disease, CHD）易感性相关。 方法学/主要结果 本研究在中国汉族人群中开展了两阶段病例对照研究。第一阶段纳入1376例冠心病患者与1376例按性别、年龄频率匹配的对照者，针对高加索人群全基因组关联研究中发现的5个全新血脂相关单核苷酸多态性（Single Nucleotide Polymorphism, SNP），分析其与中国人群冠心病发病风险的关联；随后在第二阶段（纳入1269例病例与2745例对照）中对具有显著关联的单核苷酸多态性进行验证。同时，本研究在4121例对照者中检测这5个全新基因座内的单核苷酸多态性与血脂水平的关联。本研究发现两个全新单核苷酸多态性：位于CELSR2-PSRC1-SORT1区域的rs599839，以及位于NCAN-CILP2区域的rs16996148，二者在中国人群中均与冠心病发病风险降低呈显著关联；在显性遗传模型下，其比值比（95%置信区间）分别为0.76（0.61~0.90；P=0.001）与0.67（0.57~0.77；P=3.4×10^-8）。采用显性遗传模型的多元线性回归分析显示，rs599839与低密度脂蛋白胆固醇（Low-Density Lipoprotein Cholesterol, LDL-C）水平降低显著相关（P=0.022）；rs16996148则与低密度脂蛋白胆固醇及高密度脂蛋白胆固醇（High-Density Lipoprotein Cholesterol, HDL-C）水平升高显著相关（P分别为2.9×10^-4与0.001）。 结论/意义 本研究在新发现的血脂相关基因座上，鉴定出两个全新单核苷酸多态性（rs599839与rs16996148），其在中国汉族人群中与冠心病易感性呈显著关联。