Hodoğlugil Uğur, Williamson David W, Huang Yadong, Mahley Robert W
Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA.
Atherosclerosis. 2005 Dec;183(2):199-212. doi: 10.1016/j.atherosclerosis.2005.03.004. Epub 2005 Jun 2.
The role of high levels of high density lipoprotein cholesterol (HDL-C) in protection against development of atherosclerosis is generally attributed to its role in reverse cholesterol transport, and the ATP binding cassette transporter A1 (ABCA1) is a key element of this process. We examined polymorphisms in ABCA1 in Turks, a population characterized by very low HDL-C levels. We discovered 36 variations in ABCA1 and genotyped informative polymorphisms in over 2,300 subjects. The rare alleles of C-14T and V771M polymorphisms were associated with higher HDL-C levels in men and, in combination with the rare alleles of R219K and I883M, respectively, with higher HDL-C in both sexes. Rare alleles of the C-14T and V771M polymorphisms were more frequent in the high HDL-C (>OR=40mg/dl) than in the low HDL-C group (<OR=30mg/dl) in men (P<0.05). Moreover, the T allele of C-14T had more in vitro transcriptional activity than the C allele (20-88%), depending on the cell line (P<0.05), suggesting its functionality. Haplotype construction and haplotype association with phenotype were performed in the promoter and coding region of ABCA1 separately. Analysis of the promoter haplotype block supported the association with the C-14T polymorphism. The C-14T and R219K polymorphisms were on different haplotype blocks. Analysis of the coding region structure revealed that the rare M allele of V771M was distributed predominantly among three common haplotypes, but the sum of their frequencies comprise only two-thirds of the frequency of the M allele. The rare alleles of the V771M and the I883M polymorphisms do not exist together on any of the common haplotypes. In conclusion, we describe a functional promoter polymorphism (C-14T) and a coding sequence variant (V771M) of ABCA1 and their interactions with two other variants (R219K and I883M) on plasma HDL-C levels in Turks.
高密度脂蛋白胆固醇（HDL-C）水平升高在预防动脉粥样硬化发展中的作用通常归因于其在逆向胆固醇转运中的作用，而三磷酸腺苷结合盒转运体A1（ABCA1）是这一过程的关键要素。我们研究了ABCA1基因多态性在土耳其人群中的情况，该人群的特点是HDL-C水平极低。我们在ABCA1基因中发现了36个变异，并对2300多名受试者进行了信息性多态性基因分型。C-14T和V771M多态性的罕见等位基因与男性较高的HDL-C水平相关，分别与R219K和I883M的罕见等位基因组合时，与两性较高的HDL-C水平相关。在男性中，C-14T和V771M多态性的罕见等位基因在高HDL-C组（>40mg/dl）中比在低HDL-C组（<30mg/dl）中更常见（P<0.05）。此外，根据细胞系的不同，C-14T的T等位基因比C等位基因具有更高的体外转录活性（20-88%）（P<0.05），表明其具有功能性。分别在ABCA1的启动子和编码区进行单倍型构建以及单倍型与表型的关联分析。对启动子单倍型块的分析支持了与C-14T多态性的关联。C-14T和R219K多态性位于不同的单倍型块上。对编码区结构的分析表明，V771M的罕见M等位基因主要分布在三种常见单倍型中，但其频率总和仅占M等位基因频率的三分之二。V771M和I883M多态性的罕见等位基因在任何常见单倍型上都不同时存在。总之，我们描述了ABCA1基因的一个功能性启动子多态性（C-14T）和一个编码序列变异（V771M），以及它们与另外两个变异（R219K和I883M）对土耳其人群血浆HDL-C水平的相互作用。
