REVIEW ARTICLE MTHFR gene polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis based on 16 studies Zahra Bagheri-Hosseinabadi 1 & Danyal Imani 2 & Hassan Yousefi 3 & Mitra Abbasifard 4,5 Received: 2 December 2019 /Revised: 25 February 2020 /Accepted: 5 March 2020 # International League of Associations for Rheumatology (ILAR) 2020 Abstract Rheumatoid arthritis (RA) is the most common autoimmune rheumatic disease, in which an epigenetic implication in the disease etiopathogenesis has been noted. Here in this meta-analysis, we attempted to investigate the pooled association of methylenetetra- hydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms and susceptibility to RA risk. A systematic search was performed in the main databases, including MEDLINE and Scopus to search for studies assessing the association between MTHFR gene C677T and A1298C polymorphisms and the risk of RA prior to December 2019. In this meta-analysis, 15 studies with 2165 patients and 1751 healthy controls for C677T SNP and 14 studies containing 2021 patients and 1760 healthy controls for A1298C SNP were included. A significant positive association between C677T SNP and RA risk was recognized in the dominant, recessive, and allelic model, but not TT and CT genotypes. The results indicated that the risk of RA in African population was increased under all genotype models while these results were repeated in Asian population just for recessive model, allelic model, and TT genotype. Moreover, the analysis of A1298C SNP demonstrated a significant association in overall population according to only the recessive model and CC genotype. Subgroup analysis according to the genotyping method indicated that RFLP-PCR method could impress the results of association between MTHFR gene A1298C and C677T SNPs and RA risk. The outcome of this meta-analysis indicated that MTHFR gene C677T SNP was much possibly be associated with RA risk. Keywords Meta-analysis . Methylenetetrahydrofolate reductase . Polymorphism . Rheumatoid arthritis Introduction Rheumatoid arthritis (RA) is a most common systemic and autoimmune disorder characterized by synovial inflammation, erosive articular degradation, and joint destruction, leading joint deformity and movement limitation [1]. Although the main etiology of RA is yet to be elucidated, studies demon- strated that both environmental and genetic risk factors may play a major role in the onset and progression of the disease [2]. The prevalence of the disease is almost 0.5–1% among the world population and is more frequently occurred in women than in men (sex ratio 3:1) [3, 4]. According to the most recent studies, genetic factors may contribute to approximately 60% of the total risk in susceptibility to RA [5]. The class II Human leukocyte antigen (HLA) has been identified as the most pow- erful genetic factors in susceptibility to RA [6, 7]. On the other hand, a number of non-HLA genes, such as Cytotoxic T lymphocyte-associated protein 4 (CTLA4), TNF receptor as- sociated factor 1 (TRAF1), Protein tyrosine phosphatase non- receptor type 22 (PTPN22), Peptidyl arginine deiminase 4 (PADI4), TNF alpha induced protein 3 (TNFAIP3), and Methylenetetrahydrofolate reductase (MTHFR) have been consistently associated with RA predisposition [8–13]. The folate biological function is to provide methyl groups required for metabolic processes, such as DNA methylation, synthesis, and repair. Therefore, folate deficiency can disrupt these processes [14]. MTHFR, an essential enzyme in folate * Mitra Abbasifard rh.abbasi70@gmail.com 1 Department of Clinical Biochemistry, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran 2 Department of Immunology, School of Public Health, Tehran University of Medical Sciences (TUMS), Tehran, Iran 3 Department of Biochemistry and Molecular Biology, LSUHSC, School of Medicine, New Orleans, LA, USA 4 Department of Internal Medicine, Ali-Ibn Abi-Talib Hospital, Rafsanjan University of Medical Sciences, Rafsanjan, Iran 5 Rheumatology Research Center, Tehran University of Medical Sciences (TUMS), Tehran, Iran Clinical Rheumatology https://doi.org/10.1007/s10067-020-05031-5