ALOX5AP和CYP3A5基因多态性与缺血性卒中后血栓事件的相关性

Correlation study between ALOX5AP and CYP3A5 genetic polymorphisms with susceptibility to ischemic stroke and atherothrombotic events

目的探讨基因多态性及基因-基因交互作用与缺血性卒中、卒中后血栓事件的相关性。方法采用基质辅助激光解吸附电离/飞行时间质谱法（MDLDI-TOF-MS）对396例缺血性卒中患者及378例对照者ALOX5APSG13S32（rs9551963）、SG13S42（rs4769060）、SG13S89（rs4769874）、SG13S114（rs10507391）、EPHX2 G860A（rs751141）、CYP2C9＊2 C430T（rs1799853）、CYP2C9＊3 A1075C（rs1057910）、CYP3A5 A6986G（rs776746）等5个基因8个位点的多态性进行检测。用广义多因子降维法（GMDR）检测基因与基因之间的交互作用,并对所有的缺血性卒中患者血栓事件进行12个月随访。血栓事件包括：缺血性卒中复发（RIS）和其他血管事件。结果单个基因分析表明,8个位点基因型分布在病例组和对照组比较,差异无统计学意义（P〉0.05）。但GMDR分析显示,rs10507391和rs776746存在有意义的交互作用,同时携带rs10507391 AA和rs776746GG者,缺血性卒中风险增加2.014倍（95%CI：1.896~6.299,P=0.006）,并与随访期间血栓事件发生相关。多元Cox回归分析显示,rs10507391 AA和rs776746GG的交互作用是缺血性卒中后血栓事件发生的独立危险因素（RR=2.921,95%CI：1.118~7.012,P=0.008）。结论 rs10507391和rs776746间的交互作用增加了缺血性卒中的易感性,并与缺血性卒中后血栓事件发生相关。

Objective The present study was designed to investigate the associations between genetic variations and ischemic stroke risk,the roles of gene-gene interactions in ischemic stroke,and their associations with atherothrombotic events.Methods Among 396 patients with ischemic stroke and 378 controls,we examined 8variants from 5genes,including ALOX5AP-SG13S32（rs9551963）,SG13S42（rs4769060）,SG13S89（rs4769874）,SG13S114（rs10507391）,EPHX2G860A（rs751141）,CYP2C9＊2 C430T（rs1799853）,CYP2C9＊3 A1075C（rs1057910）,and CYP3A5A6986G（rs776746）,using matrix-assisted laser desorption/ionization time of flight mass spectrometry.Gene-gene interactions were determined by the generalized multifactor dimensionality reduction（GMDR）method.All ischemic stroke patients were followed up 12 months for atherothrombotic events,including recurrent ischemic stroke and other vascular events.Results Single-gene variant analysis showed no significant differences in the genotype distributions of the 8variants between the 2 groups. However,GMDR analysis showed a significant interaction between rs10507391 and rs776746,in those cases carrying rs10507391 AA and rs776746 GG,the risk of ischemic stroke increased by 2.014times（95% confidence interval[CI],1.896-6.299;P =.006）,and the atherothrombotic events occurred more frequently in those patients during follow-up period（P〈 .001）.Multiple Cox regression analysis showed that the interaction between rs10507391 AA and rs776746 GG was an independent risk factor for atherothrombotic events（relative risk = 2.921;95% CI,1.118-7.012;P =.008）.Conclusion The interaction between rs10507391 and rs776746increases the susceptibility to ischemic stroke and is associated with atherothrombotic events in stroke patients.