凝血因子基因（F2、F5、F7、F12和F13）中九种常见多态性对他汀类药物疗效的影响：基因与他汀类药物疗效（GenHAT）研究
The effect of nine common polymorphisms in coagulation factor genes (F2, F5, F7, F12 and F13 ) on the effectiveness of statins: the GenHAT study.
作者信息
Maitland-van der Zee Anke-Hilse, Peters Bas J M, Lynch Amy I, Boerwinkle Eric, Arnett Donna K, Cheng Suzanne, Davis Barry R, Leiendecker-Foster Catherine, Ford Charles E, Eckfeldt John H
机构信息
Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht University, Utrecht, The Netherlands.
出版信息
Pharmacogenet Genomics. 2009 May;19(5):338-44. doi: 10.1097/fpc.0b013e32832933b7.
BACKGROUND
Pharmacogenetic research has shown that genetic variation may influence statin responsiveness. Statins exert a variety of beneficial effects beyond lipid lowering, including antithrombotic effects, which contribute to the risk reduction of cardiovascular disease. Statins have been shown to influence the expression of coagulation factors II, V, VII, XII and XIII.
AIM
Data from a large randomized clinical trial of pravastatin, designed to show efficacy relative to usual care, were used to investigate whether a pharmacogenetic effect of polymorphisms in genes coding for coagulation factors II, V, VII, XII and XIII is associated with reduced fatal coronary heart disease (CHD) and nonfatal myocardial infarction, combined CHD and all-cause mortality.
METHODS
The Genetics of Hypertension Associated Treatment is an ancillary study of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. The genotyped population in the lipid-lowering trial of Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial included 9624 participants randomly assigned to pravastatin or to usual care. The efficacy of pravastatin in reducing risk of all-cause mortality, CHD and nonfatal myocardial infarction and combined CHD, was compared among genotype strata by examining an interaction term in a proportional hazards model.
RESULTS
None of the polymorphisms were associated with the clinical outcomes. For the F7 (-323) ins/del polymorphism there was no interaction with pravastatin for either outcome. For both the F5 Arg506Gln G>A (rs6025) polymorphism and F7 Arg353Gln G>A (rs6046) polymorphism there were no interactions with pravastatin in relation to all-cause mortality, but there were significant interactions with combined CHD [interaction hazard ratio = 1.33, 95% confidence interval (1.01-1.76) and interaction hazard ratio = 1.92, 95% confidence interval (1.00-3.65), respectively]. There were no interactions between the polymorphisms in the other coagulation genes and pravastatin in relation to any outcome.
CONCLUSION
Polymorphisms in anticoagulation genes (F5 and F7) seem to modify the efficacy of pravastatin in reducing risk of cardiovascular events.
背景
药物遗传学研究表明，基因变异可能影响他汀类药物的反应性。他汀类药物除了降低血脂外，还具有多种有益作用，包括抗血栓形成作用，这有助于降低心血管疾病的风险。已证明他汀类药物会影响凝血因子II、V、VII、XII和XIII的表达。
目的
一项旨在显示普伐他汀相对于常规治疗疗效的大型随机临床试验数据，用于研究编码凝血因子II、V、VII、XII和XIII的基因多态性的药物遗传学效应是否与降低致命性冠心病（CHD）、非致命性心肌梗死、合并冠心病和全因死亡率相关。
方法
高血压相关治疗遗传学研究是预防心脏病发作试验中降压和降脂治疗的一项辅助研究。预防心脏病发作试验降脂试验中的基因分型人群包括9624名随机分配接受普伐他汀或常规治疗的参与者。通过检查比例风险模型中的交互项，比较了各基因型亚组中普伐他汀在降低全因死亡率、冠心病和非致命性心肌梗死以及合并冠心病风险方面的疗效。
结果
没有一种多态性与临床结局相关。对于F7（-323）插入/缺失多态性，两种结局与普伐他汀均无交互作用。对于F5 Arg506Gln G>A（rs6025）多态性和F7 Arg353Gln G>A（rs6046）多态性，与全因死亡率相比，与普伐他汀均无交互作用，但与合并冠心病存在显著交互作用[交互风险比分别为1.33，95%置信区间（1.01 - 1.76）和交互风险比为1.92，95%置信区间（1.00 - 3.65）]。其他凝血基因的多态性与普伐他汀在任何结局方面均无交互作用。
结论
抗凝基因（F5和F7）的多态性似乎会改变普伐他汀降低心血管事件风险的疗效。
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