环氧化酶基因多态性及交互作用与脑梗死患者阿司匹林抵抗相关性

The correlation between cyclooxygenase genetic polymorphisms and their interactions with aspirin resistance

目的 探讨脑梗死患者阿司匹林抵抗（AR）发生率,环氧化酶（COX）基因多态性及其间交互作用与AR相关性。方法 收集2009-08—2011-08在温州医科大学第三附属医院和德阳市人民医院住院就诊的634例急性脑梗死患者,于入院当天开始服用阿司匹林,7～10d后检测血小板聚集率,筛选出AR者及阿司匹林敏感（AS）者。采用质谱法对患者COX-1和COX-2共4个基因位点多态性进行检测。采用广义多因子降维法（GMDR）分析多基因位点交互作用。多因素Logistic回归分析AR发生的独立危险因素。结果 634例脑梗死患者发生AR者129例（20.35%）,半抵抗（ASR）者28例（4.42%）,AS者477例（75.23%）。AR组和AS组间COX-1和COX-2各基因位点基因型分布差异无统计学意义（P〉0.05）;GMDR分析显示,COX-1和COX-2基因存在交互作用,最优模型为rs3842787和rs20417两个基因位点的联合作用模型,交叉检验一致性为10/10,符号检验P=0.0116。糖尿病（OR=2.16,95%CI：1.25～4.67,P〈0.01）、rs3842787和rs20417高风险交互（OR=2.51,95%CI：1.38～5.96,P〈0.01）为发生AR的独立危险因素。结论 中国脑梗死患者AR发生率高,rs3842787和rs20417联合交互作用可能增加了AR风险,对基因与基因间的交互作用分析有助于深入研究AR的机制。

Objective To investigate the prevalence of aspirin resistance （AR） in patients with cerebral infarction ,and the correlation between cyclooxygenase （COX） genetic polymorphisms and their interaction with AR. Methods We prospectively enrolled 634 patients with cerebral infarction in the Third Affiliated Hospital of Wenzhou Medical University and People’ s Hospital of Deyang City from Aug 2009 to Aug 2011. Aspirin was administrated to every patient from the first day of admission. Platelet aggregation testing was performed after 7‐10 days of aspirin administration to screen the patients with AR or aspirin sensitive （AS） . COX‐1 （rs1236913 , rs3842787） and COX‐2 （rs689466 ,rs20417） genetic polymorphisms were measured by using mass spectrometry. Gene‐gene interactions were analyzed by using generalized multifactor dimensionality reduction （GMDR ） analysis. Logistic regression was performed to find independent risk factors of AR. Results _ Among 634 patients ,AR was detected in 129 patients （20.35% ） ,aspirin semi‐resistance （ASR） was detected in 28 patients （4.42% ） ,and AS was detected in 477 patients （75.23% ） . There were no significant differences in the genotype distributions of the 4 genetic polymorphisms between the AR group and AS group by using single‐locus analytical approach. However ,the GMDR analysis showed a significant gene‐gene interaction among rs3842787 and rs20417 ,and scored 10 for Cross‐Validation Consistency and 9 for Sign Test （P = 0.0116） . Diabetes mellitus （OR= 2.16 ,95% CI：1.25‐4.67 , P 〈 0.01） ,and the gene‐gene interaction among rs3842787 and rs20417 （OR= 2.51 ,95% CI：1.38‐5.96 , P〈 0.01） were independent risk factors of AR. Conclusions The incidence of AR is high in Chinese patients with cerebral infarction. The gene‐gene interaction among rs3842787 and rs20417 may confer higher risk for AR. The combinatorial analysis used in this study may be helpful to 〈br〉 elucidate mechanisms for AR.