Renin-angiotensin system gene polymorphisms and coronary artery disease in a large angiographic cohort: Detection of high order gene-gene interaction
Renin-angiotensin system gene polymorphisms and coronary artery disease in a large angiographic cohort: Detection of high order gene-gene interaction
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DOI：
10.1016/j.atherosclerosis.2006.09.014
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发表时间：
2007-11-01
期刊：
影响因子：
5.3
通讯作者：
Tseng, Yung-Zu
中科院分区：
文献类型：
--
作者：
Tsai, Chia-Ti;Hwang, Juey-Jen;Tseng, Yung-Zu
关于肾素-血管紧张素系统（RAS）基因多态性与冠心病（CAD）和急性心肌梗死（AMI）的关系已有许多报道，但结果不一致。在本研究中，我们使用了几种新的方法与多位点数据重新评估这个问题，在一个大的和相对同质的台湾人口。在1996年至2003年期间，共招募了1254例连续接受心导管插入术的患者（735例有记录的冠状动脉疾病，519例无）。血管紧张素转换酶基因插入/缺失（I/D）多态性;血管紧张素原基因的T174 M、M235 T、G-6A、A-20 C、G-152 A和G-217 A多态性;血管紧张素11 I型受体基因的Al 166 C多态性进行基因分型。在单位点分析中，没有位点与CAD、AMI病史和三支血管CAD相关，无论是否校正了传统CAD风险因素。对于多位点分析，我们重新建立了一个平衡的人群，对照组与传统CAD风险因素的病例单独匹配。单倍型分析发现，血管紧张素原基因单倍型在病例组和对照组之间有显著性差异（χ（2）= 31.6，P = 0.030）。此外，显著的三个位点多因素降维法检测G-217 A、M235 T和I/D基因间的相互作用（最高交叉验证一致性10.0，最低预测误差40.56%，P=0.017）和许多更高阶的基因-基因互作（16种基因型不平衡仅在对照中发现，所有这些都包括AGT、ACE和ATIR基因中的至少两种基因）。我们的研究首次证实了RAS基因多态性与CAD之间的上位性、高阶基因-基因相互作用。这些结果与传统方法所忽略的复杂疾病中多位点和多基因效应的概念是一致的。(c)2006爱思唯尔爱尔兰有限公司保留所有权利。
There have been many reports regarding the association between renin-angiotensin system (RAS) gene polymorphisms and coronary artery disease (CAD) or acute myocardial infarction (AMI), but the results are inconsistent. In the present study, we used several new approaches with multilocus data to reappraise this issue in a large and relatively homogeneous Taiwanese population. A total of 1254 consecutive patients who underwent cardiac catheterization (735 with documented coronary artery disease and 519 without) between 1996 and 2003 were recruited. Angiotensin-converting enzyme gene insertion/deletion (I/D) polymorphism; T174M, M235T, G-6A, A-20C, G-152A and G-217A polymorphisms of the angiotensinogen gene; and Al 166C polymorphism of the angiotensin 11 type I receptor gene were genotyped. In single-locus analyses, no locus was associated with CAD, history of AMI and three-vessel CAD, either with or without adjustment for conventional CAD risk factors. For multilocus analyses, we recreated a balanced population, with the controls individually matched to the cases regarding the conventional CAD risk factors. We found that the angiotensinogen gene haplotype profile was significantly different between the cases and controls (chi(2) = 31.6, P = 0.030) in haplotype analyses. Furthermore, significant three-locus (G-217A, M235T and I/D) gene-gene interactions were detected by multifactor-dimensionality reduction method (highest cross-validation consistency 10.0, lowest prediction error 40.56%, P=0.017) and many even higher order gene-gene interactions by multilocus genotype disequilibrium tests (16 genotype disequilibria exclusively found in the controls, all of which included at least two genes among AGT, ACE and AT I R genes). Our study is the first to demonstrate epistatic, high-order, gene-gene interactions between RAS gene polymorphisms and CAD. These results are compatible with the concept of multilocus and multi-gene effects in complex diseases that would be missed with conventional approaches. (c) 2006 Elsevier Ireland Ltd. All rights reserved.