Talmud Philippa J, Drenos Fotios, Shah Sonia, Shah Tina, Palmen Jutta, Verzilli Claudio, Gaunt Tom R, Pallas Jacky, Lovering Ruth, Li Kawah, Casas Juan Pablo, Sofat Reecha, Kumari Meena, Rodriguez Santiago, Johnson Toby, Newhouse Stephen J, Dominiczak Anna, Samani Nilesh J, Caulfield Mark, Sever Peter, Stanton Alice, Shields Denis C, Padmanabhan Sandosh, Melander Olle, Hastie Claire, Delles Christian, Ebrahim Shah, Marmot Michael G, Smith George Davey, Lawlor Debbie A, Munroe Patricia B, Day Ian N, Kivimaki Mika, Whittaker John, Humphries Steve E, Hingorani Aroon D
Centre for Cardiovascular Genetics, Department of Medicine, University College London, London WC1E 6JF, UK.
Am J Hum Genet. 2009 Nov;85(5):628-42. doi: 10.1016/j.ajhg.2009.10.014.
Blood lipids are important cardiovascular disease (CVD) risk factors with both genetic and environmental determinants. The Whitehall II study (n=5592) was genotyped with the gene-centric HumanCVD BeadChip (Illumina). We identified 195 SNPs in 16 genes/regions associated with 3 major lipid fractions and 2 apolipoprotein components at p<10(-5), with the associations being broadly concordant with prior genome-wide analysis. SNPs associated with LDL cholesterol and apolipoprotein B were located in LDLR, PCSK9, APOB, CELSR2, HMGCR, CETP, the TOMM40-APOE-C1-C2-C4 cluster, and the APOA5-A4-C3-A1 cluster; SNPs associated with HDL cholesterol and apolipoprotein AI were in CETP, LPL, LIPC, APOA5-A4-C3-A1, and ABCA1; and SNPs associated with triglycerides in GCKR, BAZ1B, MLXIPL, LPL, and APOA5-A4-C3-A1. For 48 SNPs in previously unreported loci that were significant at p<10(-4) in Whitehall II, in silico analysis including the British Women's Heart and Health Study, BRIGHT, ASCOT, and NORDIL studies (total n>12,500) revealed previously unreported associations of SH2B3 (p<2.2x10(-6)), BMPR2 (p<2.3x10(-7)), BCL3/PVRL2 (flanking APOE; p<4.4x10(-8)), and SMARCA4 (flanking LDLR; p<2.5x10(-7)) with LDL cholesterol. Common alleles in these genes explained 6.1%-14.7% of the variance in the five lipid-related traits, and individuals at opposite tails of the additive allele score exhibited substantial differences in trait levels (e.g., >1 mmol/L in LDL cholesterol [approximately 1 SD of the trait distribution]). These data suggest that multiple common alleles of small effect can make important contributions to individual differences in blood lipids potentially relevant to the assessment of CVD risk. These genes provide further insights into lipid metabolism and the likely effects of modifying the encoded targets therapeutically.
血脂是重要的心血管疾病（CVD）风险因素，受遗传和环境因素共同影响。怀特霍尔二世研究（n = 5592）采用以基因为中心的人类心血管疾病基因芯片（Illumina）进行基因分型。我们在16个基因/区域中鉴定出195个单核苷酸多态性（SNP），这些SNP与3种主要血脂成分和2种载脂蛋白成分相关，p值<10^(-5)，其关联性与之前的全基因组分析大致一致。与低密度脂蛋白胆固醇（LDL胆固醇）和载脂蛋白B相关的SNP位于低密度脂蛋白受体（LDLR）、前蛋白转化酶枯草溶菌素9（PCSK9）、载脂蛋白B（APOB）、钙黏蛋白相关家族成员2（CELSR2）、3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）、胆固醇酯转运蛋白（CETP）、转位蛋白40-载脂蛋白E-补体C1-C2-C4基因簇以及载脂蛋白A5-载脂蛋白A4-补体C3-载脂蛋白A1基因簇；与高密度脂蛋白胆固醇（HDL胆固醇）和载脂蛋白AI相关的SNP位于CETP、脂蛋白脂肪酶（LPL）、肝脂酶（LIPC）、载脂蛋白A5-载脂蛋白A4-补体C3-载脂蛋白A1基因簇以及ATP结合盒转运蛋白A1（ABCA1）；与甘油三酯相关的SNP位于葡萄糖激酶调节蛋白（GCKR）、锌指蛋白148（BAZ1B）、碳水化合物反应元件结合蛋白（MLXIPL）、LPL以及载脂蛋白A5-载脂蛋白A4-补体C3-载脂蛋白A1基因簇。对于怀特霍尔二世研究中p值<10^(-4)的48个位于此前未报道基因座的SNP，包括英国女性心脏与健康研究、BRIGHT、盎格鲁-斯堪的纳维亚心脏结局试验（ASCOT）以及北欧缺血性心脏病试验（NORDIL）研究（总数n>12,500）的电子分析揭示了信号转导和转录激活因子2B（SH2B3，p<2.2×10^(-6)）、骨形态发生蛋白受体2（BMPR2，p<2.3×10^(-7)）、B细胞淋巴瘤3/脊髓灰质炎病毒受体样蛋白2（BCL3/PVRL2，位于APOE侧翼；p<4.4×10^(-8)）以及BRG1相关因子（SMARCA4，位于LDLR侧翼；p<2.5×10^(-7)）与LDL胆固醇之间此前未报道的关联性。这些基因中的常见等位基因解释了五种血脂相关性状中6.1%-14.7%的变异，并且在加性等位基因评分两端的个体在性状水平上表现出显著差异（例如，LDL胆固醇差异>1 mmol/L[约为该性状分布的1个标准差]）。这些数据表明，多个小效应的常见等位基因可能对血脂的个体差异有重要贡献，这可能与心血管疾病风险评估相关。这些基因为脂质代谢以及治疗性修饰编码靶点的可能效果提供了进一步的见解。
