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

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。

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

OBJECTIVE To systematically review the association between NUDT15 R139C 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 R139C 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 R139C 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 R139C 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 R139C 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 15R139C genotype can be clinically useful for individualized therapy with mercaptopurine drugs.