Lu Hong, Inazu Akihiro, Moriyama Yuri, Higashikata Toshinori, Kawashiri Masa-Aki, Yu Wenxin, Huang Zhiping, Okamura Tomonori, Mabuchi Hiroshi
Molecular Genetics of Cardiovascular Disorders, Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Takara-machi 13-1, 920-8641, Kanazawa, Japan.
J Mol Med (Berl). 2003 Apr;81(4):246-55. doi: 10.1007/s00109-002-0414-7. Epub 2003 Mar 26.
Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters from HDL to triglyceride-rich lipoproteins. TaqIB polymorphism (B2 allele) identified in intron 1 is associated with lower plasma CETP concentrations and higher HDL cholesterol levels and may play an antiatherogenic role in humans. However, its molecular mechanism remains unclear. To evaluate the association between the promoter polymorphisms and CETP/HDL cholesterol levels, ten novel and three previously reported polymorphisms located within 3.3 kb of the CETP gene promoter were investigated in a sample of 357 elderly Japanese men. All the promoter polymorphisms were in linkage disequilibrium with each other and with TaqIB. The -2505A allele, the "S" allele of the gaaa repeat ("S" denotes gaaa=329 bp and longer, "L" denotes >329 bp) and TaqIB2 allele were significantly associated with both lower plasma CETP concentrations and higher HDL cholesterol levels whereas -971G/A and -629A/C were significantly associated with CETP concentrations but not with HDL-C levels. The 12-polymorphism haplotypes consisting of -2804, -2505, gaaa, -1930, -1674, -1129, -1046, -971, -875, -827, -629, and TaqIB were analyzed. These 12 polymorphisms generated eight main haplotypes, accounting for 86% of the observed haplotypes. The G/A/S/T/T/C/T/A/C/C/A/B2 haplotype was significantly associated with lower CETP concentrations (2.0+/-0.6 micro g/ml) and higher HDL cholesterol levels (55.1+/-12.7 mg/dl) than the other seven main haplotypes. The 5- and 3-polymorphism haplotype analyses consisting of -2505 and the gaaa repeat indicated the -2505C/A polymorphism might explain the variation in the CETP concentrations best, and the gaaa repeat and/or the -2505C/A polymorphism may independently determine the variation in HDL cholesterol levels, whereas the -629A/C and TaqIB polymorphisms were not instrumental in determining CETP concentrations as well as HDL cholesterol levels, although the latter has been frequently examined in many association studies.
胆固醇酯转运蛋白（CETP）介导胆固醇酯从高密度脂蛋白（HDL）向富含甘油三酯的脂蛋白的转运。在第1内含子中鉴定出的TaqIB多态性（B2等位基因）与较低的血浆CETP浓度和较高的HDL胆固醇水平相关，可能在人类中发挥抗动脉粥样硬化作用。然而，其分子机制仍不清楚。为了评估启动子多态性与CETP/HDL胆固醇水平之间的关联，在357名日本老年男性样本中研究了位于CETP基因启动子3.3 kb内的10个新的和3个先前报道的多态性。所有启动子多态性彼此之间以及与TaqIB均处于连锁不平衡状态。-2505A等位基因、gaaa重复序列的“S”等位基因（“S”表示gaaa=329 bp及更长，“L”表示>329 bp）和TaqIB2等位基因与较低的血浆CETP浓度和较高的HDL胆固醇水平均显著相关，而-971G/A和-629A/C与CETP浓度显著相关，但与HDL-C水平无关。分析了由-2804、-2505、gaaa、-1930、-1674、-1129、-1046、-971、-875、-827、-629和TaqIB组成的12个多态性单倍型。这12个多态性产生了8个主要单倍型，占观察到的单倍型的86%。与其他7个主要单倍型相比，G/A/S/T/T/C/T/A/C/C/A/B2单倍型与较低的CETP浓度（2.0±0.6μg/ml）和较高的HDL胆固醇水平（55.1±12.7mg/dl）显著相关。由-2505和gaaa重复序列组成的5个和3个多态性单倍型分析表明，-2505C/A多态性可能最能解释CETP浓度的变化，gaaa重复序列和/或-2505C/A多态性可能独立决定HDL胆固醇水平的变化，而-629A/C和TaqIB多态性在决定CETP浓度以及HDL胆固醇水平方面不起作用，尽管后者在许多关联研究中经常被检测。
