A META-ANALYSIS OF THE ASSOCIATION BETWEEN THE ATIC 347 C/G POLYMORPHISM AND METHOTREXATE RESPONSIVENESS AND TOXICITY IN RHEUMATOID ARTHRITIS

초록

Background: The 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC) plays a crucial role in the de novo purine synthesis pathway, and variations in this gene have been associated with altered enzymatic activity and impaired methotrexate (MTX) metabolism. The ATIC 347 C/G (rs2372536) polymorphism, which results in a threonine-to-serine substitution at position 116 of the gene, has emerged as a promising candidate for influencing MTX treatment outcomes. Objectives: The purpose of this study was to determine whether the 347 C/G polymorphism in the ATIC gene predicts the responsiveness to or toxicity of MTX in patients with rheumatoid arthritis (RA). Methods: To identify relevant publications, we searched the Medline, Embase, Cochrane, and Web of Science databases. We performed a meta-analysis of studies on the relationship between the ATIC 347 C/G polymorphism and MTX toxicity or non-responsiveness in patients with RA. Results: Thirteen studies consisting of 3,185 patients with RA satisfied our inclusion criteria. The analysis included 10 studies on MTX responsiveness and seven studies on MTX toxicity in patients with RA in connection with ATIC 347C/G polymorphism. According to our meta-analysis, the ATIC 347 GG genotype and failure to respond to MTX treatment were significantly associated (OR = 0.741, 95% CI = 0.591–0.929, p=0.009). According to stratification by ethnicity, this genotype was significantly associated with non-responsiveness to MTX in Europeans (OR=0.548, 95% CI=0.377–0.796, p=0.002) but not in Asian populations (OR=0.882, 95% CI=0.665–1.1172, p=0.388). However, analyses employing allelic, dominant, and homozygous contrast models failed to detect any relationship between the polymorphism and the failure to respond to MXT. However, the ATIC 347GG genotype and MTX toxicity were not associated (OR=1.278, 95% CI=0.937–1.745, p=0.121). Asian and European populations showed no evidence of a relationship between the ATIC 347GG genotype and MTX toxicity (OR=1.252, 95% CI=0.905–1.732, p=0.175 and OR =1.617, 95% CI=0.549–4.765, p=0.383, respectively). Conclusion: This meta-analysis revealed that ATIC 347 C/G polymorphism was related to non-responsiveness to MTX in European populations with RA. However, no significant correlation was found with MTX toxicity.