Mishra Avshesh, Srivastava Anshika, Mittal Tulika, Garg Naveen, Mittal Balraj
Department of Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow 226014, UP, India.
Department of Cardiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow 226014, UP, India.
Gene. 2014 Aug 10;546(2):309-17. doi: 10.1016/j.gene.2014.05.060. Epub 2014 May 27.
Left ventricular dysfunction (LVD) is a complex, multifactorial condition, caused by mechanical, neurohormonal, and genetic factors. We have previously observed association of renin-angiotensin-aldosterone system (RAAS), matrix metalloproteinases (MMPs) and inflammatory pathway genes with LVD. Therefore the present study was undertaken to identify the combination of genetic variants and their possible interactions contributing towards genetic susceptibility to LVD in the background of coronary artery disease (CAD).
The study included 230 healthy controls and 510 consecutive patients with angiographically confirmed CAD. Among them, 162 with reduced left ventricle ejection fraction (LVEF≤45%) were categorized as having LVD. We analyzed 11 polymorphisms of RAAS, MMPs and inflammatory pathways. Single locus analysis showed that AT1 A1166C (p value<0.001; OR=3.67), MMP9 R668Q (p value=0.007; OR=3.48) and NFKB1-94 ATTG ins/del (p value=0.013; OR=2.01) polymorphisms were independently associated with LVD when compared with both non-LVD patients and healthy controls. High-order gene-gene interaction analysis, using classification and regression tree (CART) and multifactor dimensionality reduction (MDR) revealed that AT1 A1166C and NFKB1-94 ATTG ins/del polymorphisms jointly increased the risk of LVD to great extent (p-value=0.001; OR=8.55) and best four-factor interaction model consisted of AT1 A1166C, MMP7 A-181G, MMP9 R668Q and NFKB1-94 ATTG ins/del polymorphisms with testing accuracy of 0.566 and cross validation consistency (CVC)=9/10 (permutation p<0.001) showed increased risk for LVD respectively.
AT1 A1166C independently and in combination with MMP9 R668Q and NFKB1-94 ATTG ins/del polymorphisms plays important role in conferring genetic susceptibility to LVD in CAD patients.
左心室功能障碍（LVD）是一种复杂的多因素疾病，由机械、神经激素和遗传因素引起。我们之前观察到肾素-血管紧张素-醛固酮系统（RAAS）、基质金属蛋白酶（MMPs）和炎症通路基因与LVD有关联。因此，本研究旨在确定基因变异的组合及其可能的相互作用，这些因素在冠状动脉疾病（CAD）背景下对LVD的遗传易感性有影响。
该研究纳入了230名健康对照者和510名经血管造影证实患有CAD的连续患者。其中，162名左心室射血分数降低（LVEF≤45%）的患者被归类为患有LVD。我们分析了RAAS、MMPs和炎症通路的11种多态性。单基因座分析显示，与非LVD患者和健康对照者相比，AT1 A1166C（p值<0.001；OR=3.67）、MMP9 R668Q（p值=0.007；OR=3.48）和NFKB1-94 ATTG插入/缺失（p值=0.013；OR=2.01）多态性与LVD独立相关。使用分类与回归树（CART）和多因素降维法（MDR）进行的高阶基因-基因相互作用分析显示，AT1 A1166C和NFKB1-94 ATTG插入/缺失多态性共同在很大程度上增加了LVD的风险（p值=0.001；OR=8.55），最佳的四因素相互作用模型由AT1 A1166C、MMP7 A-181G、MMP9 R668Q和NFKB1-94 ATTG插入/缺失多态性组成，其测试准确性为0.566，交叉验证一致性（CVC）=9/10（置换p<0.001），分别显示出LVD风险增加。
AT1 A1166C单独以及与MMP9 R668Q和NFKB1-94 ATTG插入/缺失多态性联合，在赋予CAD患者LVD遗传易感性方面起重要作用。
