Associations between C677T and A1298C polymorphisms of MTHFR and susceptibility to rheumatoid arthritis: a systematic review and meta-analysis

Methylenetetrahydrofolatereductase (MTHFR) is an important enzyme involved in folate metabolism and DNA synthesis. Although a number of studies have examined the association of the MTHFR C677T and A1298C polymorphisms with susceptibility to rheumatoid arthritis (RA), the conclusions are controversial. A comprehensive literature search using PubMed, Embase, the Cochrane Library, CNKI and Wanfang databases was conducted for relevant studies on the association between MTHFR polymorphisms and RA risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using fixed- and random-effect models. In total, 1854 cases and 1689 controls from 12 studies and 1525 cases and 1455 controls from 10 studies were included for the C677T and A1298C polymorphisms, respectively. Pooled results indicated that both C677T and A1298C polymorphisms were associated with RA susceptibility (C677T: TT vs. CC, OR = 1.31, 95% CI = 1.02–1.67, P = 0.032; TC vs. CC, OR = 1.32, 95% CI = 1.02–1.70, P = 0.032; TT + TC vs. CC, OR = 1.38, 95% CI = 1.07–1.78, P = 0.014; T vs. C, OR = 1.29, 95% CI = 1.06–1.57, P = 0.011; A1298C: CC vs. CA + AA: OR = 1.58, 95% CI = 1.20–2.06, P = 0.001). Further stratification based on ethnicity and geographic region indicated an association between the MTHFR C677T SNP and the risk of RA in Caucasian and patients in Africa. However, there is no evidence of significant association between A1298C polymorphism and RA risk in Caucasian or population in Africa. This meta-analysis indicates that MTHFR C677T and A1298C polymorphisms could be predictors of risk of RA and warrants validation in large and well-designed prospective studies.