Liu Yue-Ping, Wu Hai-Yan, Yang Xiang, Xu Han-Qing, Li Yong-Chuan, Shi Da-Chuan, Huang Jun-Fu, Huang Qing, Fu Wei-Ling
Department of Laboratory Medicine, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
PLoS One. 2015 Mar 23;10(3):e0121745. doi: 10.1371/journal.pone.0121745. eCollection 2015.
Thiopurine drugs are well established treatments in the management of inflammatory bowel disease (IBD), but their use is limited by significant adverse drug reactions (ADRs). Thiopurine S-methyltransferase (TPMT) is an important enzyme involved in thiopurine metabolism. Several clinical guidelines recommend determining TPMT genotype or phenotype before initiating thiopurine therapy. Although several studies have investigated the association between TPMT polymorphisms and thiopurine-induced ADRs, the results are inconsistent. The purpose of this study is to evaluate whether there is an association between TPMT polymorphisms and thiopurine-induced ADRs using meta-analysis.
We explored PubMed, Web of Science and Embase for articles on TPMT polymorphisms and thiopurine-induced ADRs. Studies that compared TPMT polymorphisms with-ADRs and without-ADRs in IBD patients were included. Relevant outcome data from all the included articles were extracted and the pooled odds ratio (OR) with corresponding 95% confidence intervals were calculated using Revman 5.3 software.
Fourteen published studies, with a total of 2,206 IBD patients, which investigated associations between TPMT polymorphisms and thiopurine-induced ADRs were included this meta-analysis. Our meta-analysis demonstrated that TPMT polymorphisms were significantly associated with thiopurine-induced overall ADRs and bone marrow toxicity; pooled ORs were 3.36 (95%CI: 1.82-6.19) and 6.67 (95%CI: 3.88-11.47), respectively. TPMT polymorphisms were not associated with the development of other ADRs including hepatotoxicity, pancreatitis, gastric intolerance, flu-like symptoms and skin reactions; the corresponding pooled ORs were 1.27 (95%CI: 0.60-2.71), 0.97 (95%CI: 0.38-2.48), 1.82 (95%CI: 0.93-3.53), 1.28 (95%CI: 0.47-3.46) and 2.32 (95%CI: 0.86-6.25), respectively.
Our meta-analysis demonstrated an association of TPMT polymorphisms with overall thiopurine-induced ADRs and bone marrow toxicity, but not with hepatotoxicity, pancreatitis, flu-like symptoms, gastric intolerance and skin reactions. These findings suggest that pretesting the TPMT genotype could be helpful in clinical practice before initiating thiopurine therapy. However, white blood cell count analysis should be the mainstay for follow-up.
硫嘌呤类药物是治疗炎症性肠病（IBD）的常用药物，但其使用受到严重药物不良反应（ADR）的限制。硫嘌呤S-甲基转移酶（TPMT）是参与硫嘌呤代谢的一种重要酶。多项临床指南建议在开始硫嘌呤治疗前确定TPMT基因型或表型。尽管多项研究调查了TPMT基因多态性与硫嘌呤诱导的ADR之间的关联，但结果并不一致。本研究的目的是通过荟萃分析评估TPMT基因多态性与硫嘌呤诱导的ADR之间是否存在关联。
我们在PubMed、Web of Science和Embase数据库中检索关于TPMT基因多态性与硫嘌呤诱导的ADR的文章。纳入比较IBD患者中TPMT基因多态性与发生ADR和未发生ADR情况的研究。提取所有纳入文章的相关结局数据，并使用Revman 5.3软件计算合并优势比（OR）及相应的95%置信区间。
本荟萃分析纳入了14项已发表的研究，共2206例IBD患者，这些研究调查了TPMT基因多态性与硫嘌呤诱导的ADR之间的关联。我们的荟萃分析表明，TPMT基因多态性与硫嘌呤诱导的总体ADR和骨髓毒性显著相关；合并OR分别为3.36（95%CI：1.82 - 6.19）和6.67（95%CI：3.88 - 11.47）。TPMT基因多态性与其他ADR的发生无关，包括肝毒性、胰腺炎、胃部不耐受、流感样症状和皮肤反应；相应的合并OR分别为1.27（95%CI：0.60 - 2.71）、0.97（95%CI：0.38 - 2.48）、1.82（95%CI：0.93 - 3.53）、1.28（95%CI：0.47 - 3.46）和2.32（95%CI：0.86 - 6.25）。
我们的荟萃分析表明，TPMT基因多态性与硫嘌呤诱导的总体ADR和骨髓毒性相关，但与肝毒性、胰腺炎、流感样症状、胃部不耐受和皮肤反应无关。这些发现表明，在开始硫嘌呤治疗前进行TPMT基因型预检测在临床实践中可能会有帮助。然而，白细胞计数分析应作为随访的主要手段。
