McCaskie Pamela A, Beilby John P, Chapman Caroline M L, Hung Joseph, McQuillan Brendan M, Thompson Peter L, Palmer Lyle J
Laboratory for Genetic Epidemiology, Western Australian Institute for Medical Research, UWA Centre for Medical Research, University of Western Australia, Nedlands, WA, 6009, Australia.
Hum Genet. 2007 May;121(3-4):401-11. doi: 10.1007/s00439-007-0326-2. Epub 2007 Feb 8.
High-density lipoprotein cholesterol (HDL-C) is a known inverse predictor of coronary heart disease (CHD) and is thus a potential therapeutic target. Cholesteryl ester transfer protein (CETP) is a key protein in HDL-C metabolism such that elevated CETP activity is associated with lower HDL-C. Currently available HDL-C raising drugs are relatively ineffective and evidence suggesting the role of CETP in HDL-C levels has promoted the development of CETP inhibitors as potential therapeutic agents for CHD. We investigated three SNPs in the CETP gene in two cross-sectional community-based populations (n = 1,574 and 1,109) and a population of 556 CHD patients to determine if reduced CETP activity due to genetic variations in the CETP gene would increase HDL-C levels and reduce the risk of CHD. CETP genotypes and haplotypes were tested for association with lipid levels, CETP activity and risk of CHD. Multivariate analysis showed the common AAB2 haplotype defined by the G-2708A, C-629A and TaqIB polymorphisms, was consistently associated with reduced CETP activity and increased HDL-C levels. A mean increase in HDL-C levels of 0.16-0.24 mmol/l was observed in individuals with two copies of the AAB2 haplotype relative to non AAB2 carriers across all three populations (P < 0.001). A case-control study of males indicated no association between single SNPs or haplotypes and the risk of CHD. These results suggest that raising HDL-C via CETP inhibition may not alter risk of CHD. Randomized control trials are needed to determine whether CETP inhibition will in reality reduce risk of CHD by raising HDL-C.
高密度脂蛋白胆固醇（HDL-C）是已知的冠心病（CHD）反向预测指标，因此是一个潜在的治疗靶点。胆固醇酯转运蛋白（CETP）是HDL-C代谢中的关键蛋白，CETP活性升高与HDL-C降低相关。目前可用的升高HDL-C的药物相对无效，而表明CETP在HDL-C水平中作用的证据推动了CETP抑制剂作为CHD潜在治疗药物的开发。我们在两个基于社区的横断面人群（n = 1574和1109）以及556例CHD患者群体中研究了CETP基因中的三个单核苷酸多态性（SNP），以确定CETP基因的遗传变异导致的CETP活性降低是否会增加HDL-C水平并降低CHD风险。对CETP基因型和单倍型进行了与血脂水平、CETP活性和CHD风险的关联测试。多变量分析显示，由G-2708A、C-629A和TaqIB多态性定义的常见AAB2单倍型始终与CETP活性降低和HDL-C水平升高相关。在所有三个人群中，相对于非AAB2携带者，具有两份AAB2单倍型拷贝的个体的HDL-C水平平均升高0.16 - 0.24 mmol/l（P < 0.001）。一项针对男性的病例对照研究表明，单个SNP或单倍型与CHD风险之间无关联。这些结果表明，通过抑制CETP升高HDL-C可能不会改变CHD风险。需要进行随机对照试验来确定抑制CETP是否真的会通过升高HDL-C降低CHD风险。
