服用非甾体消炎药或阿司匹林后产生上消化道损伤风险与基因多态性相关性的Meta分析

doi:10.12114/j.issn.1007-9572.2019.00.292

摘要/Abstract

摘要： 背景　非甾体消炎药（NSAIDs）是一类不含有甾体结构的抗炎药物，在临床中应用广泛。对于长期服用人群，药物不良反应需要加以关注，其中最主要的是上消化道损伤（UGI）。然而UGI在不同人群间存在差异，这可能与基因多态性相关。目的　分析NSAIDs或阿司匹林UGI与基因多态性的关系。方法　计算机检索PubMed、EMBase、Cochrane Library、中国知网、万方数据知识服务平台、维普网及中国生物医学文献数据库，检索时间从建库至2018-01-08。纳入服用NSAIDs或阿司匹林UGI与基因多态性相关性的研究。完成资料提取及文献质量评价。采用Haploview（version 4.2）、R（version 3.4.3）及STATA（version 14.0）软件进行Meta分析及生物信息学相关分析。结果　共纳入文献19篇。Meta分析结果显示，SLCO1B1基因rs2306283（A>G）突变在日本人群中，杂合子模型显示了会增加阿司匹林UGI发生的风险〔OR=1.53，95%CI（1.02，2.30），P=0.04〕；SLCO1B1基因rs4149056（T>C）突变在日本人群中，单基因〔OR=0.50，95%CI（0.33，0.75），P<0.05〕、杂合子〔OR=0.49，95%CI（0.32，0.76），P<0.05〕和显性模型〔OR=0.48，95%CI（0.31，0.73），P<0.05〕显示了会降低阿司匹林UGI发生的风险；CYP2C9基因rs1799853（C>T）突变在高加索人群中，单基因〔OR=1.42，95%CI（1.11，1.80），P<0.05〕、杂合子〔OR=1.38，95%CI（1.05，1.83），P=0.02〕、显性模型〔OR=1.44，95%CI（1.10，1.88），P=0.01〕显示了会增加NSAIDs UGI发生的风险（P<0.05）。在STRING数据库中罗列所有与NSAIDs UGI潜在相关的蛋白进行相互作用分析，发现这些相关联蛋白从功能上主要分为两大类型，包括药物的代谢转运相关蛋白以及炎性反应相关蛋白。结论　本研究证实了SLCO1B1基因rs2306283（A>G）突变会增加阿司匹林UGI发生的风险，CYP2C9基因rs1799853（C>T）突变会增加NSAIDs UGI发生的风险，同时也提出了SLCO1B1基因rs4149056（T>C）突变具有对阿司匹林UGI的保护性作用。

关键词: 非甾类消炎药；阿司匹林；胃肠道损伤；多态性, 单核苷酸；CYP2C9基因；SLCO1B1基因；Meta分析

Abstract: Background　Non-steroidal anti-inflammatory drugs （NSAIDs） are a class of anti-inflammatory drugs without steroidal structure widely used in clinic practice.Adverse drug reactions need to be concerned for long-term users，the most important of which is upper gastrointestinal injury （UGI）．However，UGT incidence is different among populations，which may be due to genetic polymorphism.Objective　To identify the association of gene polymorphisms with risk of UGI after using NSAIDs/aspirin.Methods　A systematic literature search was conducted in PubMed，EMBase，Cochrane Library，Chinese National Knowledge Infrastructure，Wanfang Data Knowledge Service Platform，VIP，China Biology Medicine disc up to January 8，2018，to identify potential relevant studies about association between genetic polymorphisms and NSAIDs/aspirin-induced UGI.Data extraction and quality evaluation were performed.Meta and bioinformatic analysis was implemented with Haploview 4.2，R 3.4.3，and STATA 14.0.Results　Nineteen studies were included.Meta-analysis showed that SLCO1B1 gene rs2306283 （A>G） mutation in Japanese heterozygote model increased the risk of aspirin-induced UGI 〔OR=1.53，95%CI（1.02，2.30），P=0.04〕.SLCO1B1 gene rs4149056 （T>C） mutation in Japanese showed that single gene 〔OR=0.50，95%CI（0.33，0.75），P<0.05〕，heterozygote 〔OR=0.49，95%CI（0.32，0.76），P<0.05〕 and dominant model 〔OR=0.48，95%CI（0.31，0.73），P<0.05〕 could reduce the risk of aspirin-induced UGI.The mutation of CYP2C9 gene rs1799853 （C>T） in Caucasian population showed that single gene 〔OR=1.42，95%CI（1.11，1.80），P<0.05〕，heterozygote 〔OR=1.38，95%CI（1.05，1.83），P=0.02〕，dominant model 〔OR=1.44，95%CI（1.10，1.88），P=0.01〕 could increase the risk of NSAIDs-induced UGI.The interaction analysis of all the proteins potentially associated with NSAIDs-induced UGI in STRING database showed that these proteins could be divided into two major functional types，including drug metabolic transport-related proteins and inflammatory response-related proteins.Conclusion　Our study confirms that the rs2306283 （A>G） mutation in SLCO1B1 gene may increase the risk of aspirin-induced UGI，the rs1799853 （C>T）mutation in CYP2C9 gene may increase the risk of NSAIDs-induced UGI，and the rs4149056 （T>C）mutation in SLCO1B1 gene exerts a protective effect against aspirin-induced UGI.

Key words: Non-steroidal anti-inflammatory drugs；Aspirin；Upper gastrointestinal injury；Polymorphism, single nucleotide；CYP2C9 gene；SLCO1B1 gene；Meta-analysis

孙晓君,郭世磊. 服用非甾体消炎药或阿司匹林后产生上消化道损伤风险与基因多态性相关性的Meta分析[J]. 中国全科医学, 2019, 22(23): 2866-2873. DOI: 10.12114/j.issn.1007-9572.2019.00.292.
SUN Xiaojun,GUO Shilei. Association between Genetic Polymorphisms and Upper Gastrointestinal Injury Risk after Using NSAIDs/Aspirin：a Meta-analysis　[J]. Chinese General Practice, 2019, 22(23): 2866-2873. DOI: 10.12114/j.issn.1007-9572.2019.00.292.

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