Kyriakou Theodosios, Hodgkinson Conrad, Pontefract David E, Iyengar Srikanth, Howell W Martin, Wong Yuk-ki, Eriksson Per, Ye Shu
Human Genetics Division, School of Medicine, University of Southampton, Southampton, UK.
Arterioscler Thromb Vasc Biol. 2005 Feb;25(2):418-23. doi: 10.1161/01.ATV.0000149379.72018.20. Epub 2004 Nov 4.
Loss-of-function mutations of the ATP-binding cassette transporter A1 (ABCA1) gene cause Tangier disease, a rare genetic disorder with accumulation of lipid-laden macrophages and increased risk of atherosclerosis. Common variants of this gene may be a genetic factor for atherosclerosis in the general population. This study was performed to test the reported association between the -565C>T polymorphism and atherosclerosis severity and to investigate whether this variant per se had an effect on promoter activity of the ABCA1 gene.
A cohort of patients with coronary atherosclerosis were genotyped for the -565C>T polymorphism. Logistic regression analyses showed that homozygotes of the -565T allele had greatest mean number of diseased coronary arteries, particular in nonsmokers. Real-time reverse-transcriptase polymerase chain reaction showed that in atherosclerotic plaques removed from patients undergoing endarteretomy, ABCA1 expression levels were lowest in those who had the T/T genotype and highest in those of the C/C genotype. Transfection and reporter assays demonstrated that in cultured macrophages, the -565T allelic promoter had a lower activity in driving gene expression than the -565C allelic promoter. Electrophoretic mobility shift assays displayed differential binding of nuclear proteins to the 2 alleles.
These results indicate that the -565C>T polymorphism has an allele-specific effect on ABCA1 gene expression and provide further evidence of a genotypic effect on coronary atherosclerosis severity. The study showed that the ABCA1 gene -565C>T polymorphism was associated with severity of coronary atherosclerosis in a cohort of patients from Southern England and that this sequence variant per se had an effect on promoter activity of the ABCA1 gene. The data support the notion that common ABCA1 gene variants can contribute to interindividual variability in atherosclerosis susceptibility and severity.
ATP结合盒转运蛋白A1（ABCA1）基因的功能丧失突变会导致丹吉尔病，这是一种罕见的遗传性疾病，其特征为脂质负载巨噬细胞的积累以及动脉粥样硬化风险增加。该基因的常见变异可能是普通人群动脉粥样硬化的遗传因素。本研究旨在验证所报道的-565C>T多态性与动脉粥样硬化严重程度之间的关联，并研究该变异本身是否对ABCA1基因的启动子活性有影响。
对一组冠状动脉粥样硬化患者进行-565C>T多态性基因分型。逻辑回归分析显示，-565T等位基因的纯合子患冠状动脉疾病的平均数量最多，尤其是在非吸烟者中。实时逆转录聚合酶链反应表明，在接受动脉内膜切除术患者切除的动脉粥样硬化斑块中，T/T基因型患者的ABCA1表达水平最低，C/C基因型患者的ABCA1表达水平最高。转染和报告基因分析表明，在培养的巨噬细胞中，-565T等位基因启动子驱动基因表达的活性低于-565C等位基因启动子。电泳迁移率变动分析显示核蛋白与这两个等位基因的结合存在差异。
这些结果表明，-565C>T多态性对ABCA1基因表达具有等位基因特异性影响，并为基因型对冠状动脉粥样硬化严重程度的影响提供了进一步证据。该研究表明，ABCA1基因-565C>T多态性与英格兰南部一组患者的冠状动脉粥样硬化严重程度相关，且该序列变异本身对ABCA1基因的启动子活性有影响。数据支持常见的ABCA1基因变异可导致个体间动脉粥样硬化易感性和严重程度差异的观点。
