MTHFR polymorphisms in autoimmune diseases: Mechanistic and clinical perspectives

The methylenetetrahydrofolate reductase (MTHFR) gene encodes a crucial enzyme in folate metabolism, serving as a central regulator of homocysteine homeostasis and one‑carbon metabolic pathways. This review synthesizes current evidence on the mechanistic and clinical implications of two common MTHFR polymorphisms, C677T and A1298C, in autoimmune pathogenesis. We critically examine their contributions to inflammatory responses, endothelial dysfunction, immune imbalance, and epigenetic modifications. Furthermore, we analyze population-specific associations between these variants and susceptibility to eight autoimmune disorders, genotype-phenotype correlations related to clinical manifestations and comorbidities, as well as pharmacogenomic interactions influencing response to methotrexate therapy. By integrating genetic, molecular, and clinical insights, this review highlights the translational potential of MTHFR genotyping for improving risk stratification and personalized treatment strategies in autoimmune and immune-mediated inflammatory conditions.