Interaction of genes from influx-metabolism-efflux pathway and their influence on methotrexate efficacy in rheumatoid arthritis patients among Indians

Abstract

Objective: Methotrexate (MTX) is the drug of choice for rheumatoid arthritis (RA) but is effective only in around 60% of treated patients. Bioavailability of MTX may be a major determinant of response status and this may be governed by variations in MTX receptor and transporter genes and genes responsible for polyglutamation and deconjugation. We investigated the contribution of single nucleotide polymorphisms (SNPs) in RFC, FOLR1, FPGS, GGH and MDR1 genes to MTX response in RA patients from North India. Methods: RA patients recruited using American College of Rheumatology criteria, were categorized into good and poor responders to MTX, based on disease activity score. A total of 17 SNPs from the above mentioned genes were genotyped and tested for association with MTX response using Χ ² test; logistic regression along with clinical variables; and gene-gene interaction using multifactor dimensionality reduction (MDR). Results: One novel synonymous SNP Ala324Ala (972 G>A) was identified in RFC gene. The CT genotype of C3435T in MDR1 gene conferred almost twice the risk of poor response [Χ²=5.85, P=0.01, odds ratio (95% confidence interval)=1.97 (1.13-3.42)] and was retained in binary logistic regression [B=0.66, P=0.025, adjusted odds ratio (95% confidence interval)=1.93(1.093.42)]. Significant interaction between SNPs in GGH and MDR1 genes seems promising. Conclusion: Interactions between genes coding for deconjugation and transporter seem to be important determinants of MTX response in RA but replication and functional studies would be confirmatory.