Impact of MTHFR C677T and A1298C gene polymorphisms on MTX drug toxicity and efficacy profile of RA patients in North India

Abstract Objective To investigate the effect of two different methylenetetrahydrofolate (MTHFR) gene loci C677T and A1298C polymorphisms on Rheumatoid arthritis (RA) and their association in response to methotrexate (MTX) therapy. Subjects and methods 110 individuals (60 RA patients and 50 healthy controls) were enrolled from different regions of north India. MTX drug response was evaluated by questionnaire data analysis, disease activity score (DAS-28) and analysis of hepatic, renal and other serological parameters. MTHFR C677T and A1298C polymorphisms were genotyped using restriction fragment length polymorphism- polymerase chain reaction (RFLP-PCR). Independent t-test was applied to compare the means and ANOVA with Bonferroni correction for multiple comparison of genotypically classified groups. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by applying χ2 test, p-value  Results The study found significant differences in all the serological parameters of controls and RA patients except protein and serum SGPT. Elevated transaminases, triglycerides, cholesterol, creatinine, C-reactive protein (CRP), uric acid and albumin are the indicators of MTX adverse effects along with disease severity. Questionnaire analysis showed loss of appetite, weak digestion, low BMI, and weight loss are common features in all the patients after starting MTX therapy. Significant association was found between 677TT genotype with elevated levels of triglycerides. While other parameters such as SGOT, SGPT, CRP, uric acid and cholesterol were insignificantly higher in patients with 677TT polymorphism. 1298CC polymorphism was associated with high CRP levels and 1298 AC with higher triglycerides along with cholesterol in RA patients. However, in controls, only albumin showed significant association with 1298AA genotype. Association of MTHFR C677T polymorphism was insignificant (677CT- OR: 0.905, 95%CI: 0.355–2.307; 677TT- OR: 1.035, 95%CI: 0.338–3.989; p-value = 1) and A1298C polymorphism was also insignificant (1298AC- OR: 0.562, 95%CI: 0.200–1.575, p-value = .4; & 1298CC- OR: 0.502, 95%CI: 0.146–1.717 with p-value = .403) with RA. Conclusion The results of this study suggest that none of these alleles are predictive for RA disease susceptibility. However, it has a significant impact on its severity with respect to CRP, triglycerides and cholesterol.