阿片类药物致便秘与基因多态性的相关性  

Study on the correlation between opioid-induced constipation and gene polymorphism

作　　者：杨静 张新宇[3] 郑磊 管玉瑶 常温来 林忠琨 张雅慧 付正[1] YANG Jing;ZHANG Xinyu;ZHENG Lei;GUAN Yuyao;CHANG Wenlai;LIN Zhongkun;ZHANG Yahui;FU Zheng(Dept.of Pharmacy,Shandong Medical College,Jinan 250031,China;Dept.of Pharmacy,Shandong Provincial Third Hospital,Jinan 250031,China;School of Medical and Pharmaceutical Science,Ocean University of China,Shandong Qingdao 266000,China;Dept.of Pharmacy,Shandong Provincial Hospital,Jinan 250031,China)

机构地区：[1]山东医学高等专科学校药学系,济南250031 [2]山东省立第三医院药学部,济南250031 [3]中国海洋大学医药学院,山东青岛266000 [4]山东省立医院药学部,济南250031

出　　处：《中国药房》2023年第9期1104-1108,共5页China Pharmacy

基　　金：山东省医药卫生科技发展计划项目(No.2017WS101);山东省药品不良反应监测中心委托项目(No.2021sdadrky03);山东省医学会治疗药物监测科研基金(No.YXH2020ZX047);济南市科技计划(后补助)项目(No.202134016)。

摘　　要：目的探讨基因多态性对阿片类药物致便秘的影响。方法首先通过检索指南、数据库及循证医学资料等筛选出与阿片类药物致便秘相关的目标基因,随后纳入100例接受阿片类药物进行镇痛治疗的癌痛患者,并根据用药后是否出现便秘分为试验组和对照组,每组各50例。利用PCR或荧光原位杂交法对目标基因进行检测;使用SNPStats程序进行Hardy-Weinberg平衡检验、基因多态性与阿片类药物致便秘的相关性分析,采用多因素Logistic回归分析阿片类药物致便秘发生的相关预测因素,绘制受试者工作特征(ROC)曲线分析各预测因素在预测阿片类药物致便秘方面的效能。结果筛选出的目标基因有CYP2D6、CYP3A5*3、ABCB1、OPRM1。基因型检测结果显示,CYP2D6(rs1065852、rs1135822、rs16947、rs28371725、rs28371735)、CYP3A5*3(058rs776746)、ABCB1(062rs1045642)、OPRM1(047rs1799971)等位基因频率分布均符合Hardy-Weinberg平衡检验。相关性分析结果显示,试验组患者CYP3A5*3(058rs776746,A>G)中的GG、AG型,OPRM1(047rs1799971,A>G)中的AA、AG型占比显著高于对照组(P<0.05)。多因素Logistic回归分析结果显示,用药时间及CYP3A5*3、OPRM1基因多态性可作为患者发生阿片类药物致便秘的预测因素(P<0.05)。ROC曲线分析结果显示,用药时间及CYP3A5*3、OPRM1基因多态性的ROC曲线下面积分别为0.648、0.640、0.670,最佳截断值分别为124.0、0.5、0.5。结论CYP3A5*3(058rs776746,A>G)GG、AG型,OPRM1(047rs1799971,A>G)AA、AG型与阿片类药物致便秘具有相关性,且上述基因型可能是患者使用阿片类药物致便秘的预测因素,同时还需要关注用药时间较长患者的便秘发生情况。OBJECTIVE To investigate the effect of gene polymorphism on opioid-induced constipation.METHODS The target genes related to opioid-induced constipation were screened out through searching guidelines,databases and evidence-based medical data,and then 100 cancer pain patients who received opioid drugs for analgesia were included as the study subjects.According to whether there were adverse effects of constipation after medication or not,they were divided into test group and control group,with 50 cases in each group.The target gene was detected by PCR or fluorescence in situ hybridization.The SNPStats program was used to carry out Hardy-Weinberg balance test and correlation analysis between gene polymorphism and opioid-induced constipation.The multivariate Logistic regression analysis was used to explore the relevant predictive factors of opioid-induced constipation,and receiver operating characteristic(ROC)curve of subjects was drawn to analyze the effectiveness of each predictive factor in predicting opioid-induced constipation.RESULTS CYP2D6,CYP3A5*3,ABCB1 and OPRM1 were selected as target genes for detection.The results of genotype detection showed that the frequency distribution of CYP2D6(rs1065852,rs1135822,rs16947,rs28371725,rs28371735),CYP3A5*3(058rs776746),ABCB1(062rs1045642),OPRM1(047rs1799971)alleles were consistent with Hardy-Weinberg balance test.The correlation analysis results showed that the proportion of genotype GG and AG in CYP3A5*3(058rs776746,A>G)and genotype AA and AG in OPRM1(047rs1799971,A>G)of patients was significantly higher in test group than that in the control group(P<0.05).Multivariate Logistic regression analysis showed that medication duration,CYP3A5*3 and OPRM1 gene polymorphism could be used as predictors of opioidinduced constipation in patients(P<0.05).The ROC curve analysis results showed that the areas under the ROC curves for medication duration and CYP3A5*3,OPRM1 gene polymorphism were 0.648,0.640 and 0.670,respectively,with the optimal cutoff values of 124.0,0.5 and 0.5,resp

关 键 词：阿片类药物 基因多态性 药物不良反应 便秘 个体化用药 

分 类 号：R971[医药卫生—药品]