title: Association between Thiopurine S-Methyltransferase Polymorphisms and Azathioprine-Induced Adverse Drug Reactions in Patients with Autoimmune Diseases: A Meta-Analysis.
abstract: OBJECTIVE
  Azathioprine (AZA) is widely used as an immunosuppressive drug in autoimmune diseases, but its use is limited by significant adverse drug reactions (ADRs). Thiopurine S-methyltransferase (TPMT) is an important enzyme involved in AZA metabolism. Several clinical guidelines recommend determining TPMT genotype or phenotype before initiating AZA therapy. Although several studies have investigated the association between TPMT polymorphisms and AZA-induced ADRs, the results are inconsistent. The purpose of this study is to evaluate whether there is an association between TPMT polymorphisms and AZA-induced ADRs using meta-analysis.
  
  
  METHODS
  We explored PubMed, Web of Science and Embase for articles on TPMT polymorphisms and AZA-induced ADRs. Studies that compared TPMT polymorphisms with-ADRs and without-ADRs in patients with autoimmune diseases were included. Relevant outcome data from all the included articles were extracted and the pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated using Revman 5.3 software.
  
  
  RESULTS
  Eleven published studies, with a total of 651 patients with autoimmune diseases, investigated associations between TPMT polymorphisms and AZA-induced ADRs, were included in this meta-analysis. Our meta-analysis demonstrated that TPMT polymorphisms were significantly associated with AZA-induced overall ADRs, bone marrow toxicity and gastric intolerance; pooled ORs were 3.12 (1.48-6.56), 3.76 (1.97-7.17) and 6.43 (2.04-20.25), respectively. TPMT polymorphisms were not associated with the development of hepatotoxicity; the corresponding pooled OR was 2.86 (95%CI: 0.32-25.86). However, the association in GI subset could be driven by one single study. After this study was excluded, the OR was 2.11 (95%CI: 0.36-12.42); namely, the association became negative.
  
  
  CONCLUSIONS
  Our meta-analysis demonstrated an association of TPMT polymorphisms with overall AZA-induced ADRs, bone marrow toxicity and gastric intolerance, but not with hepatotoxicity. The presence of the normal TPMT genotypes cannot preclude the development of ADRs during AZA treatment, TPMT genotyping prior to commencing AZA therapy cannot replace, may augment, the current practice of regular monitoring of the white blood cell. Because of small sample sizes, large and extensive exploration was required to validate our findings.
authors.affiliation: Department of Laboratory Medicine, Southwest Hospital, Third Military Medical University, Chongqing, China.|Department of Laboratory Medicine, 477th Hospital of PLA, Xiangyang City, Hubei Province, China.
authors.forename: Yue-Ping
authors.initials: YP
authors.lastname: Liu
authors.affiliation: Department of Laboratory Medicine, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Han-Qing
authors.initials: HQ
authors.lastname: Xu
authors.affiliation: Department of Laboratory Medicine, 477th Hospital of PLA, Xiangyang City, Hubei Province, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Laboratory Medicine, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Laboratory Medicine, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Laboratory Medicine, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Wei-Ling
authors.initials: WL
authors.lastname: Fu
authors.affiliation: Department of Laboratory Medicine, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Huang
mesh_terms: D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000235:genetics*; D001379:Azathioprine / Q000009:adverse effects* / Q000627:therapeutic use; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D008780:Methyltransferases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D007166:Immunosuppressive Agents; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine