Polymorphism of genes involved in methotrexate pathway: Predictors of response to methotrexate therapy in Indian rheumatoid arthritis patients

Abstract

Introduction: The adenosine pathway is one of the ways through which methotrexate (MTX) ameliorates inflammation. We therefore explored an association of polymorphism of genes involved in adenosine and MTX metabolic pathways with response to MTX. Methods: Association of polymorphism in 7 genes (rs2236225 [MTHFD1 1958G<A], rs17602729 [AMPD1 G<A], rs1127354 [ITPA C<A], rs1431131 [TGFBR2 A<T], rs2372536 [ATIC C<G], rs11188513 [ENTPD1 C<T] and rs5751876 [ADORA2A T<C]) with efficacy of MTX was studied in Indian rheumatoid arthritis (RA) patients. The patients, classified by European League Against Rheumatology (EULAR)/American College of Rheumatology (ACR) 2010 criteria, were DMARD (disease-modifying antirheumatic drug)-naïve, with Disease Activity Score (DAS28) <3.2. After 4 months of MTX monotherapy, patients were classified as responders (R) or non-responders (NR) based on EULAR response criteria. Genotyping was done by TaqMan 5' nuclease assay and association of gene polymorphisms with response to MTX was determined by Chi-squared test. Results: Two hundred and twenty-six patients (86% female, median age 40 [interquartile range, IQR = 17.25] years), with disease duration of 24 (IQR = 38.25) months and DAS28-C-reactive protein score of 4.61 (IQR = 1.34) were enrolled. After therapy, 186 patients were classified as R and 40 as NR. GG genotype of ATIC (P = .01, odds ratio [OR] 2.56, 95% CI, 1.04-6.30) and CC genotype of ITPA (P = .009, OR 1.34, 95% CI 1.02-1.76) genes were found to be associated with the response. On binary logistic regression analysis, GG genotype of ATIC and CC of ITPA genes were independent predictors of the response. Conclusion: Polymorphisms of ATIC and ITPA genes alone or with clinical variables were associated with response to MTX therapy in Indian RA patients.