Wang Ruili, Liu Baogang, Li Jiapeng, Xu Jiamin, Wang Xiaoling, Zhao Zhigang, Zhao Libo
Clinical Research Center, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, People's Republic of China.
Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Capital Medical University, Beijing, People's Republic of China.
Drug Des Devel Ther. 2019 Aug 5;13:2729-2744. doi: 10.2147/DDDT.S210512. eCollection 2019.
As a common immunosuppressive and anticancer drug, thiopurine has achieved remarkable clinical success. However, higher inter-individual dose variability and unpredictable toxicity still challenge its use in clinical practices. Some studies indicate that polymorphisms are associated with this variation, but specific correlation remains controversial. This meta-analysis assessed the association between three polymorphisms of and thiopurine-induced toxicities.
Three databases were electronically searched: PubMed, Embase, and Web of Science. Only case-control studies and cohort studies were eligible. The overall pooled ORs and corresponding 95% CIs were used to represent the results.
We included 16 studies that focus on c.415C > T, c.52G > A, and 36_37insGGAGTC polymorphisms in patients treated with thiopurine. Significant associations between c.415C > T polymorphism and leukopenia were found in all genetic models (TC/TT vs CC, OR: 7.64, 95% CI: (6.19, 9.44), <0.00001; TT vs CC/TC, OR: 29.66, 95% CI: (12.31, 71.46), <0.00001; TT vs CC, OR: 45.60, 95% CI: (18.84, 110.37), <0.00001; TC vs CC, OR: 6.41, 95% CI: (5.19, 7.94), <0.00001; TT vs TC, OR: 6.38, 95% CI: (2.59, 15.72), <0.00001), early/late leukopenia (in recessive and co-dominant model), leukopenia (grade 3-4), and severe hair loss in all genetic models. Besides, c.52G > A and 36_37insGGAGTC polymorphisms were also significantly associated with leukopenia. No significant association between c.415C > T polymorphism and early/late leukopenia in the Chinese population was determined in the co-dominant model (TC vs CC).
c.415C > T polymorphism could increase the risk of leukopenia, early/late leukopenia, leukopenia (grade 3-4), and severe hair loss. Meanwhile, c.52G > A and c.36_37insGGAGTC mutations also probably increase the risk of leukopenia. Preemptive tests for polymorphisms are highly recommended to individualize the treatment of thiopurine for a better outcome with less toxicity.
硫唑嘌呤作为一种常用的免疫抑制剂和抗癌药物，已在临床上取得了显著成效。然而，个体间剂量差异较大且毒性难以预测，这仍对其临床应用构成挑战。一些研究表明，基因多态性与这种差异有关，但具体的相关性仍存在争议。本荟萃分析评估了[基因名称]的三种多态性与硫唑嘌呤诱导的毒性之间的关联。
通过电子检索三个数据库：PubMed、Embase和Web of Science。仅纳入病例对照研究和队列研究。采用总体合并比值比（OR）及相应的95%置信区间（CI）来表示结果。
我们纳入了16项针对接受硫唑嘌呤治疗患者的[基因名称] c.415C>T、c.52G>A和36_37insGGAGTC多态性的研究。在所有遗传模型中均发现c.415C>T多态性与白细胞减少症之间存在显著关联（TC/TT vs CC，OR：7.64，95%CI：(6.19, 9.44)，<0.00001；TT vs CC/TC，OR：29.66，95%CI：(12.31, 71.46)，<0.00001；TT vs CC，OR：45.60，95%CI：(18.84, 110.37)，<0.00001；TC vs CC，OR：6.41，95%CI：(5.19, 7.94)，<0.00001；TT vs TC，OR：6.38，95%CI：(2.59, 15.72)，<0.00001），以及早期/晚期白细胞减少症（隐性和共显性模型）、3-4级白细胞减少症和所有遗传模型中的严重脱发。此外，c.52G>A和36_37insGGAGTC多态性也与白细胞减少症显著相关。在共显性模型（TC vs CC）中，未确定中国人群中c.415C>T多态性与早期/晚期白细胞减少症之间存在显著关联。
c.415C>T多态性可能会增加白细胞减少症、早期/晚期白细胞减少症、3-至4级白细胞减少症和严重脱发的风险。同时，c.52G>A和c.36_37insGGAGTC突变也可能增加白细胞减少症的风险。强烈建议对[基因名称]多态性进行预先检测，以使硫唑嘌呤治疗个体化，从而在降低毒性的同时获得更好的疗效。
