Klerkx Anke H E M, Tanck Michael W T, Kastelein John J P, Molhuizen Henri O F, Jukema J Wouter, Zwinderman Aeilko H, Kuivenhoven Jan Albert
Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
Hum Mol Genet. 2003 Jan 15;12(2):111-23. doi: 10.1093/hmg/ddg013.
The TaqIB polymorphism in intron 1 of the cholesteryl ester transfer protein (CETP) gene is associated with plasma CETP concentration, high-density lipoprotein cholesterol (HDL-C) and coronary artery disease (CAD). These associations are generally thought to arise from linkage disequilibrium between TaqIB and (an)other functional polymorphism(s). To identify putative functional sites, we investigated phenotypic associations of TaqIB and four tightly linked polymorphisms (novel -2708G-->A and +784CCC-->A, and previously identified -971G-->A and -629C-->A) in 709 males with CAD (REGRESS). In addition to genotype analyses, a novel method to estimate haplotype effects was used to examine the individual and joint effects of these DNA variants on CETP concentration and HDL-C. All polymorphisms were associated with CETP concentration and HDL-C, except for -971 with HDL-C. Stepwise regression and haplotype analyses indicated that only -629 was independently associated with HDL-C. Similar analyses additionally indicated that -2708 and -629 were independently associated with CETP concentration, whereby the most frequent alleles acted in a cumulative manner. Nonetheless, detailed haplotype analysis revealed that a 3-polymorphism haplotype model consisting of -2708, -629 and -971 explained the variation in CETP concentration best. The involvement of -971 could be due to interaction effects that were observed between -971 and both -629 (P<0.001) and -2708 (P=0.047). In conclusion, the TaqIB polymorphism is not instrumental in determining CETP or HDL-C levels, but is a marker for the -629 promoter variant. Our analyses, furthermore, indicate that the -2708 and -971 polymorphisms are likely to play a role in determining CETP concentration.
胆固醇酯转运蛋白（CETP）基因第1内含子中的TaqIB多态性与血浆CETP浓度、高密度脂蛋白胆固醇（HDL-C）及冠状动脉疾病（CAD）相关。一般认为这些关联源于TaqIB与其他功能性多态性之间的连锁不平衡。为了确定假定的功能位点，我们在709例CAD男性患者（REGRESS研究）中研究了TaqIB及4个紧密连锁的多态性（新发现的-2708G→A和+784CCC→A，以及先前鉴定的-971G→A和-629C→A）的表型关联。除了基因型分析，还使用了一种估计单倍型效应的新方法来检验这些DNA变异对CETP浓度和HDL-C的个体及联合效应。所有多态性均与CETP浓度和HDL-C相关，但-971与HDL-C无关。逐步回归和单倍型分析表明，只有-629与HDL-C独立相关。类似分析还表明，-2708和-629与CETP浓度独立相关，其中最常见的等位基因以累积方式起作用。然而，详细的单倍型分析显示，由-2708、-629和-971组成的三多态性单倍型模型对CETP浓度变化的解释最佳。-971的参与可能是由于观察到-971与-629（P<0.001）和-2708（P=0.047）之间的相互作用效应。总之，TaqIB多态性在决定CETP或HDL-C水平方面不起作用，而是-629启动子变异的一个标记。此外，我们的分析表明，-2708和-971多态性可能在决定CETP浓度方面起作用。
