Cholesterol ester transfer protein, interleukin-8, peroxisome proliferator activator receptor alpha, and toll-like receptor 4 genetic variations and risk of incident nonfatal myocardial infarction and ischemic stroke
Cholesterol ester transfer protein, interleukin-8, peroxisome proliferator activator receptor alpha, and toll-like receptor 4 genetic variations and risk of incident nonfatal myocardial infarction and ischemic stroke
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DOI：
10.1016/j.amjcard.2008.02.052
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发表时间：
2008-06-15
影响因子：
2.8
通讯作者：
Psaty, Bruce M.
中科院分区：
文献类型：
--
作者：
Enquobahrie, Daniel A.;Smith, Nicholas L.;Psaty, Bruce M.
参与氧化应激、炎症及其相互作用的候选基因的变异可能与动脉粥样硬化起源的疾病相关。我们研究了胆固醇酯转移蛋白（CETP）、白细胞介素8（IL 8）、过氧化物酶体增殖物激活物受体α（PPARA）和Toll样受体4（TLR 4）基因变异与非致命性心肌梗死（MI）或缺血性卒中的独立和联合相关性。在一项基于人群的病例对照研究中，患者（848例MI和368例缺血性卒中）和对照组（2，682例）均来自华盛顿州西部健康组的绝经后女性和高血压男性/女性成员。使用成对连锁不平衡从基因测序数据中选择代表全基因变异的共同标签单核苷酸多态性（SNPs; n = 34）。单倍型推断使用修改的期望最大化算法。多变量逻辑回归分析在对数加性模型中评估个体单倍型和SNP-疾病关联。全球单倍型测试评估了整体基因-疾病关联。逻辑回归用于评估基因-基因相互作用。错误发现率和排列检验分别用于评估独立关联和相互作用的多重检验调整。总体而言，PPARA和TLR 4基因的全基因变异与MI相关。PPARA SNP的次要等位基因rs 4253623与较高的MI风险相关（比值比1.25，95%置信区间1.08至1.46），而TLR 4 SNP的次要等位基因rs 1927911与较低的MI风险相关（比值比0.88，95%置信区间0.77至0.99）。没有基因内或基因-基因相互作用与MI或缺血性卒中风险相关。总之，本研究中发现的潜在SNP-疾病关联是新的，需要进一步研究。(c)2008年爱思唯尔公司All rights reserved.
Variations in candidate genes participating in oxidative stress, inflammation, and their interactions are potentially associated with diseases of atherosclerotic origin. We investigated independent and joint associations of variations in cholesterol ester transfer protein (CETP), interleukin-8 (IL8), peroxisome proliferator activator receptor-alpha (PPARA), and Toll-like receptor 4 (TLR4) genes with incident nonfatal myocardial infarction (MI) or ischemic stroke. In a population-based case-control study, patients (848 with MI and 368 with ischemic stroke) and controls (2,682) were recruited from postmenopausal women and hypertensive men/women who were members of Group Health in western Washington State. Common tag single-nucleotide polymorphisms (SNPs; n = 34) representing gene-wide variations were selected from gene sequencing data using pairwise linkage disequilibrium. Haplotypes were inferred using a modified expectation maximization algorithm. Multivariate logistic regression evaluated individual haplotype and SNP-disease associations in log-additive models. Global haplotype tests assessed overall gene-disease associations. Logic regression was used to evaluate gene-gene interactions. False discovery rates and permutation tests were used for multiple testing adjustment in evaluating independent associations and interactions, respectively. Overall, gene-wide variations in PPARA and TLR4 genes were associated with MI. The minor allele of the PPARA SNP, rs4253623, was associated with a higher risk of MI (odds ratio 1.25, 95% confidence interval 1.08 to 1.46), whereas the minor allele of the TLR4 SNP, rs1927911, was associated with a lower risk of MI (odds ratio 0.88, 95% confidence interval 0.77 to 0.99). No within-gene or gene-gene interaction was associated with MI or ischemic stroke risk. In conclusion, potential SNP-disease associations identified in the present study are novel and need further investigation. (c) 2008 Elsevier Inc. All rights reserved.