Association between thiopurine S-methyltransferase polymorphisms and thiopurine-induced adverse drug reactions in patients with inflammatory bowel disease: a meta-analysis

Yue-Ping Liu; Hai-Yan Wu; Xiang Yang; Han-Qing Xu; Yong-Chuan Li; Da-Chuan Shi; Jun-Fu Huang; Qing Huang; Wei-Ling Fu

doi:10.1371/journal.pone.0121745

Association between thiopurine S-methyltransferase polymorphisms and thiopurine-induced adverse drug reactions in patients with inflammatory bowel disease: a meta-analysis

PLoS One. 2015 Mar 23;10(3):e0121745. doi: 10.1371/journal.pone.0121745. eCollection 2015.

Authors

Yue-Ping Liu¹, Hai-Yan Wu¹, Xiang Yang¹, Han-Qing Xu¹, Yong-Chuan Li¹, Da-Chuan Shi¹, Jun-Fu Huang¹, Qing Huang¹, Wei-Ling Fu¹

Affiliation

¹ Department of Laboratory Medicine, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.

Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Drug-Related Side Effects and Adverse Reactions / enzymology*
Drug-Related Side Effects and Adverse Reactions / genetics*
Humans
Inflammatory Bowel Diseases / drug therapy*
Methyltransferases / genetics*
Polymorphism, Genetic*
Purines / adverse effects*
Purines / therapeutic use

Substances

Purines
Methyltransferases
thiopurine methyltransferase

Grants and funding

This work was supported by grants from National Natural Science Foundation of China (General Program, No.31370853). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.