Variants of toll-like receptor 4 modify the efficacy of statin therapy and the risk of cardiovascular events
Variants of toll-like receptor 4 modify the efficacy of statin therapy and the risk of cardiovascular events
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DOI：
10.1161/01.cir.0000068311.40161.28
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发表时间：
2003-05-20
期刊：
影响因子：
37.8
通讯作者：
Jukema, JW
中科院分区：
文献类型：
--
作者：
Boekholdt, SM;Agema, WRP;Jukema, JW
背景-动脉粥样硬化越来越被认为是一种慢性炎症过程。我们研究了Toll样受体4（TLR4）的遗传变异是否与先天免疫受损和颈动脉粥样硬化的进展相关，也与冠状动脉粥样硬化和预测心血管事件的风险。方法和结果TLR4基因的两种多态性（Asp299Gly和Thr399Ile）在655名男性血管造影证实的冠状动脉粥样硬化。所有患者都参加了一项前瞻性的降胆固醇试验，评估对冠状动脉疾病的影响，并随机分配到普伐他汀或安慰剂组，为期2年。在基线风险因素、治疗或试验期间血脂、脂蛋白或血管造影测量的变化方面，基因定义的亚组之间无显著差异。基因型与动脉粥样硬化的进展无关。在普伐他汀组中，299Gly携带者在随访期间心血管事件的风险低于非携带者（2.0%对11.5%，P = 0.045）。在非携带者中，普伐他汀使心血管事件的风险从18.1%降低到11.5%（P = 0.03），而在299Gly携带者中，这种风险从29.6%显著降低到2.0%（相互作用P = 0.0002，P = 0.025）。结论-在有冠心病记录的有症状男性中，TLR4 Asp299Gly多态性与心血管事件的风险相关。这种变异也改变了普伐他汀预防心血管事件的疗效，使得该变异等位基因的携带者从普伐他汀治疗中获益更大。
Background-Atherosclerosis is increasingly considered to be a chronic inflammatory process. We examined whether genetic variants of the toll-like receptor 4 (TLR4), which are correlated with impaired innate immunity and with progression of carotid atherosclerosis, are also associated with coronary atherosclerosis and predict the risk of cardiovascular events.Methods and Results-Two polymorphisms of the TLR4 gene (Asp299Gly and Thr399Ile) were determined in 655 men with angiographically documented coronary atherosclerosis. All patients participated in a prospective cholesterol-lowering trial evaluating the effect on coronary artery disease and were randomly assigned to either pravastatin or placebo for 2 years. There were no significant differences between genetically defined subgroups with respect to baseline risk factors, treatment, or in-trial changes of lipid, lipoprotein, or angiographic measurements. Genotype was not associated with progression of atherosclerosis. In the pravastatin group, 299Gly carriers had a lower risk of cardiovascular events during follow-up than noncarriers (2.0% versus 11.5%, P=0.045). Among noncarriers, pravastatin reduced the risk of cardiovascular events from 18.1% to 11.5% (P=0.03), whereas among 299Gly carriers this risk was strikingly reduced from 29.6% to 2.0% (P=0.0002, P=0.025 for interaction).Conclusions-Among symptomatic men with documented coronary artery disease, the TLR4 Asp299Gly polymorphism was associated with the risk of cardiovascular events. This variant also modified the efficacy of pravastatin in preventing cardiovascular events, such that carriers of the variant allele had significantly more benefit from pravastatin treatment.