伊立替康致3~4级中性粒细胞减少与UGT1A1基因多态性相关性的Meta分析

摘要

目的:系统评价UGT1A1基因多态性与伊立替康致3~4级中性粒细胞减少不良反应的相关性,为临床提供循证参考.方法:计算机检索中国期刊全文数据库、万方数据库、中文科技期刊数据库、PubMed、EMBase、Science direct与Cochrane图书馆,收集UGT1A1*28和UGT1A1*6基因多态性与伊立替康致3~4级中性粒细胞减少的相关研究,对符合纳入标准的研究进行提取资料和质量评价,采用Rev Man 5.3统计软件进行Meta分析.结果:共纳入29项研究,合计2408例患者.UGT1A1*28基因型分为野生型TA 6/6(UGT1A1*1/*1)和突变型TA 6/7(UGT1A1*1/*28)、TA 7/7(UGT1A1*28/*28),UGT1A1*6基因型分为野生型GG和突变型GA、AA.Meta分析结果显示,UGT1A1*28和UGT1A1*6突变型患者3~4级中性粒细胞减少发生率显著高于野生型,差异有统计学意义[UGT1A1*28:OR=1.92,95%CI(1.52,2.44),P<0.001;UGT1A1*6:OR=2.49,95%CI(1.46,4.26),P<0.001];伊立替康中、高剂量时UGT1A1*28和UGT1A1*6突变型患者3~4级中性粒细胞减少发生率显著高于野生型,差异有统计学意义[UGT1A1*28:OR=2.06,95%CI(1.57,2.70),P<0.001);UGT1A1*6:OR=1.92,95%CI(1.35,2.74),P<0.001];而伊立替康低剂量时UGT1A1*28和UGT1A1*6突变型患者3~4级中性粒细胞减少发生率与野生型比较差异无统计学意义[UGT1A1*28:OR=1.20,95%CI(0.70,2.08),P=0.51;UGT1A1*6:OR=3.19,95%CI(0.85,11.89),P=0.08].结论:伊立替康的中、高剂量使用时,UGT1A1*28和UGT1A1*6突变基因会增加肿瘤患者重度中性粒细胞减少风险;但在低剂量时,基因多态性与中性粒细胞减少的相关性无明确的相关性.%OBJECTIVE:To evaluate the association between UGT1A1 gene polymorphism and irinotecan-induced 3-4 degree neutropenia,and to provide evidenced-based reference for clinical treatment. METHODS:Retrieved from CJFD,Wanfang data-base,VIP,PubMed,EMBase,Science direct and Cochrane library,related studies about UGT1A1*28 and UGT1A1*6 gene polymorphism and irinotecan-induced 3-4 degree neutropenia were collected. After data extraction and quality evaluation of included studies,Meta-analysis was conducted by using Review Man 5.3 software. RESULTS:A total of 29 studies were included,involv-ing 2408 patients. UGT1A1*28 includ wild genotype TA 6/6(UGT1A1*1/*1)and mutations genotype TA 6/7(UGT1A1*1/*28)、TA 7/7(UGT1A1*28/*28),UGT1A1*6 includ wild genotype GG and mutations genotype GA、AA. Results of Meta-analysis showed:the incidence of 3-4 degree neutropenia in UGT1A1*28 and UGT1A1*6 mutations genotype were significantly higher than wild genotype,with statistical significance [UGT1A1*28:OR=1.92,95%CI(1.52,2.44),P<0.001;UGT1A1*6:OR=2.49, 95%CI(1.46,4.26),P<0.001]. Using medium-dose and high-dose of irinotecan,the incidence of 3-4 degree neutropenia in UGT1A1*28 and UGT1A1*6 mutations genotype were significantly higher than wild genotype,with statistical significance [UGT1A1*28:OR=2.06,95%CI(1.57,2.70),P<0.001);UGT1A1*6:OR=1.92,95%CI(1.35,2.74),P<0.001]. Using low-dose of irinotecan,there was no statistical significance in the incidence of 3-4 degree neutropenia between UGT1A1*28,UGT1A1*6 mutations genotype and wild genotype [UGT1A1*28:OR=1.20,95%CI(0.70,2.08),P=0.51;UGT1A1*6:OR=3.19,95%CI (0.85,11.89),P=0.08]. CONCLUSIONS:Using medium-dose and high-dose of irinotecan,UGT1A1*28 and UGT1A1*6 muta-tions will increase the risk of severe neutropenia in cancer patients. Using low-dose of irinotecan,there is no clear correlation be-tween gene polymorphism and the neutropenia.