Year: 2025
Type: article
Study design: Observational Study
Abstract: Objectives Methylenetetrahydrofolate reductase (MTHFR) generates the active form of folic acid required for homocysteine metabolism. The C677T variant in MTHFR reduces enzymatic activity, increases homocysteine levels, and is associated with risk of several neurological diseases. However, its link to multiple sclerosis (MS) risk remains uncertain. We therefore investigated the association of this variant with risk and severity of MS. Methods We obtained genetic associations of C677T with homocysteine levels ( n = 1210), MS risk (meta-analysis of three datasets: 43,069 cases), and MS severity (12,584 cases). We report associations of the C677T variant with MS risk and severity, and performed sensitivity analyses to assess genetic confounding. Results There was strong statistical evidence for an association of the C677T variant with risk of MS (pooled odds ratio [OR] of MS per homocysteine-raising allele 0.91, 95 % confidence interval [CI] 0.89–0.93, P = 7.59 × 10 −14 ). The OR when scaled to an SD increase in genetically determined homocysteine levels due to MTHFR perturbation was 0.73 (95 % CI 0.66–0.79, P = 7.27 × 10 −14 ). Colocalization analyses supported C677T as a shared causal variant for MS and homocysteine levels at the MTHFR locus. By contrast, no association was found between C677T and MS severity ( P = 0.92). Discussion These results support a novel biological hypothesis linking impaired MTHFR function to protection from MS. Further research is needed to elucidate the underlying mechanism and explore potential therapeutic implications.
Source: Journal of Neuroimmunology
Authors: Iyas Daghlas, John V. Pluvinage, Dipender Gill
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,360
OpenAlex ID: W4415680904