Genetic polymorphisms associated with therapeutic response and adverse effects to methotrexate in Taiwanese patients with rheumatoid arthritis: a real-world, hospital-based study

Although methotrexate (MTX) is extensively utilized in management of rheumatoid arthritis (RA), its pharmacogenomics are still unclear. This study explores the genetic determinants impacting MTX's effectiveness and adverse effects in Taiwanese patients with RA, aiming to enhance understanding of RA treatment and pharmacogenetics. A retrospective analysis of 1,948 RA patients receiving MTX treatment from January 2009 to January 2022, using data from the Taiwan Precision Medicine Initiative (TPMI) at Taichung Veterans General Hospital. Among these patients, 872 who required treatment with biologic disease modifying anti-rheumatic drugs (bDMARDs) or targeted synthetic DMARDs (tsDMARDs) were classified as MTX 'non-response', while the 1,076 patients treated without these agents were categorized as MTX 'response'. Chi-square analysis was employed to compare the carrier ratio of 82 selected MTX-associated SNPs from previous literature. Logistic regression models were utilized to explore associations between genetic variants and the risk of non-response and adverse effects, with adjustments made for potential confounding factors. Significant genetic markers influencing MTX response included ABCC1 rs212090, which predicted better MTX efficacy (p = 0.016), and ABCC3 rs2277624 and rs4148416, linked to lower MTX response rates (p = 0.004 and p = 0.023). SNPs in ADORA3 rs2298191 and ABCC4 rs7317112 were linked to a higher risk of thrombocytopenia (p = 0.045 and p = 0.049). Our study identifies genetic variations ABCC1 and ABCC3 related to MTX efficacy in treating RA, while SNPs in ADORA3 and ABCC4 are associated with the side effect of thrombocytopenia. These insights offer a foundation for tailoring individual treatment plans based on genetic profiles.