Toll-like receptor 4 gene Asp299Gly polymorphism is associated with reductions in vascular inflammation, angiographic coronary artery disease, and clinical diabetes
Toll-like receptor 4 gene Asp299Gly polymorphism is associated with reductions in vascular inflammation, angiographic coronary artery disease, and clinical diabetes
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DOI：
10.1016/j.ahj.2004.05.049
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发表时间：
2004-12-01
影响因子：
4.8
通讯作者：
Anderson, JL
中科院分区：
文献类型：
--
作者：
Kolek, MJ;Carlquist, JF;Anderson, JL
背景冠状动脉疾病（CAD）和越来越多的糖尿病被认为具有炎症基础。膜Toll样受体（TLR）激活上调炎症的信号通路。我们评估是否Asp 299 Gly多态性的TLR 4基因，这损害炎症反应，与减少血管炎症（评估C-反应蛋白[CRP]）和CAD和糖尿病的风险降低。方法1894例无急性心肌梗死进行冠状动脉造影进行了研究。基因分型通过实时聚合酶链反应进行。CAD定义为大于或等于70%狭窄。糖尿病由患者的转诊医生诊断。采用荧光偏振免疫法测定CRP。回归分析校正了传统的心脏风险因素，结果患者平均年龄为64+/-11岁，69%为男性。Asp 299 Gly基因型频率AA=0.911（n=1725），AG=0.086（n=164），GG=0.003（n=5），符合Hardy-Weinberg平衡。CRP在G等位基因携带者中（中位数=1.11 mg/dL）低于野生型（AA）受试者（1.23 mg/dL，校正后P= 0.044）。G等位基因携带者的CAD（65% vs. 73%，OR=0.67，CI=0.46-0.99，调整后P= 0.048）和糖尿病（11% vs. 18%，OR=0.63，CI=0.42-0.95，调整后P= 0.029）患病率也较低，这在多变量logistic回归分析中持续存在。299 Gly携带不影响临床结果，也不与他汀类therapeutic.Conclusions相互作用TLR 4 299 Gly等位基因与CRP水平降低，平行，血管造影CAD和临床糖尿病的风险降低。这些发现表明，先天免疫反应性的下调可以有益地改变CAD和糖尿病的风险，并可能为遗传风险分层和治疗靶向提供新的基础。
Background Coronary artery disease (CAD) and, increasingly, diabetes are recognized as having an inflammatory basis. Membrane toll-like receptors (TLRs) activate signaling pathways that up-regulate inflammation. We evaluated whether the Asp299Gly polymorphism in the TLR4 gene, which impairs inflammatory responses, is associated with reduced vascular inflammation (assessed by C-reactive protein [CRP]) and a decreased risk for CAD and diabetes.Methods 1894 patients without acute myocardial infarction undergoing coronary angiography were studied. Genotyping was performed by real-time polymerase chain reaction. CAD was defined as greater than or equal to70% stenosis. Diabetes was diagnosed by patients' referring physicians. CRP was measured by fluorescence polarization immunoassay. Regression analyses adjusted for traditional cardiac risk,factors.Results Patients averaged 64+/-11 years of age, and 69% were male. Asp299Gly genotype frequencies were: AA=0.911 (n=1725), AG=0.086 (n=164), and GG=0.003 (n=5), in keeping with Hardy-Weinberg equilibrium. CRP was lower among G-allele carriers (median=1.11 mg/dL)than wild-type (AA) subjects (1.23 mg/dL, adjusted P=.044). G-allele carriers also had a lower prevalence of CAD (65% vs. 73%, OR=0.67, CI=0.46-0.99, adjusted P=.048) and diabetes (11% vs. 18%, OR=0.63, CI=0.42-0.95, adjusted P=.029), which persisted in multivariate logistic regression analyses. 299Gly carriage did not affect clinical outcomes nor interact with statin therapy.Conclusions The TLR4 299Gly allele was associated with reduced CRP levels and, in parallel, a decreased risk of angiographic CAD and clinical diabetes. These findings suggest that down-regulation of innate immune responsiveness could beneficially modify CAD and diabetes risk and might provide a novel basis for genetic risk stratification and therapeutic targeting.