亚洲炎症性肠病患者中NUDT15 R139C基因多态性与巯嘌呤类药物诱导的白细胞减少的Meta分析

Association between NUDT15 R139C polymorphism and thiopurine-induced leukopenia in Asian inflammatory bowel disease: A Meta-analysis

目的:系统评价亚洲炎症性肠病患者中NUDT15 R139C基因多态性与巯嘌呤类药物诱导的白细胞减少的关系。方法:计算机检索PubMed、Embase、Web of Science、CNKI和万方等数据库中NUDT15 R139C基因多态性与巯嘌呤诱导的白细胞减少的相关研究,检索时间均为建库至2018年6月。由2位评价员独立筛选文献、提取资料并评价纳入研究的质量,采用Revman 5.3软件进行Meta分析。结果:共纳入8个研究,3 676例炎症性肠病患者,Meta分析结果表明:NUDT15 R139C纯合突变与杂合突变者发生白细胞减少的风险显著高于野生型患者,差异有显著性([TT&CC:OR=73.24, 95%CI(32.81,163.47),P<0.000 01;TC&CC:OR=5.99, 95%CI(4.97,7.22),P<0.000 01;TT+TC&CC:OR=7.33 95%CI(6.12,8.78),P<0.000 01]);此外还发现,NUDT15 R139C纯合突变与杂合突变者发生早期白细胞减少的风险[TT&CC:OR=56.90, 95%CI(25.40,127.49),P<0.000 01;TC&CC:OR=2.20, 95%CI(1.42,3.41),P=0.000 2;TT+TC&CC:OR=6.19, 95%CI(2.76, 13.85),P=0.002]、严重白细胞减少的风险[TT&CC:OR=34.32,95%CI(16.74,70.37),P<0.000 01;TC&CC:OR=2.50, 95%CI(1.54,4.05),P=0.000 2;TT+TC&CC:OR=4.87 95%CI(3.13,7.59),P<0.000 01]均较野生型患者高,差异有显著性。结论:在炎症性肠病患者中,NUDT15 R139C基因突变患者使用巯嘌呤药物发生白细胞减少、早期白细胞减少、严重白细胞减少的风险显著高于野生型,临床上NUDT 15R139C基因型的测定可对巯嘌呤类药物个体化治疗提供有力的帮助。

OBJECTIVE To systematically review the association between NUDT15 R139 C polymorphism and thiopurine-induced leukopenia in Asian inflammatory bowel disease(IBD).METHODS A search of PubMed,Embase,Web of Science,CNKI,and Wanfang databases for studies related to NUDT15 R139 C gene polymorphism and mercaptopurine-induced leukopenia was conducted until June 2018.Two independent investigators reviewed relevant studies,extracted data from included studies,assess the quality of included studies by Newcastle-Ottawa Quality Assessment Scale(NOS)and finally a meta-analysis was conducted by Revman 5.3 software.RESULTS Eight independent studies(3676 subjects)were included in this meta-analysis.The results revealed that NUDT15 R139 C homozygous mutation and heterozygous mutation could significantly increase the risk of leukopenia than that in the wild type.[TT&CC:OR=73.24,95%CI(32.81,163.47,P<0.000 01;TC&CC:OR=5.99,95%CI(4.97,7.22),P<0.000 01;TT+TC&CC:OR=7.33 95%CI(6.12,8.78),P<0.000 01]);in addition,it was found that the risk of early leukopenia in patients with NUDT15 R139 C homozygous mutation and heterozygous mutation was significantly higher than that in wild-type patients in terms of early leukopenia[TT&CC:OR=56.90,95%CI(25.40,127.49),P<0.000 01;TC&CC:OR=2.27,95%CI(1.48,3.48),P=0.000 2;TT+TC&CC:OR=6.19,95%CI(2.76,13.85),P=0.002]and severe leukopenia(TT&CC:OR=34.32,95%CI(16.74,70.37),P<0.000 01;TC&CC:OR=2.50,95%CI(1.54,4.05),P=0.000 2;TT+TC&CC:OR=4.87 95%CI(3.13,7.59),P<0.00001)CONCLUSION Patients with NUDT15 R139 C mutations have a significantly higher risk of leukopenia,early leukopenia,and severe leukopenia with mercaptopurine than wild-type patients with inflammatory bowel disease,and the determination of the NUDT 15 R139 C genotype can be clinically useful for individualized therapy with mercaptopurine drugs.