The Effects of the MTHFR 677C>T (rs1801133) Genetic Variant on Susceptibility and Disability in Multiple Sclerosis Patients are Mediated by Homocysteine but not Folate Levels

Abstract We investigated whether the MTHFR 677C>T (rs1801133) variant and plasma homocysteine and folate are associated with multiple sclerosis (MS), disability, disability progression, and inflammatory biomarkers. We included 163 MS patients categorized using the Expanded Disability Status Scale (EDSS) as mild (EDSS<3) and moderate/high (EDSS≥3) disability, and 226 healthy controls. Disability progression was evaluated using Multiple Sclerosis Severity Score (MSSS) and the MTHFR 677C>T was genotyped using real time polymerase chain reaction. The levels of some inflammatory biomarkers and inflammatory activity index (IAI) were determined. There was no association between the MTHFR 677 C>T genotypes and MS, EDSS, and MSSS (p>0.05). Plasma folate and homocysteine were higher and adiponectin was lower in MS patients than controls (p<0.001). Moreover, 21.8% of the EDSS variance was explained by age, IAI and C-reactive protein (CRP) (all positively associated); 10.9% of the MSSS variance was predicted by IAI and CRP (both positively) and vitamin D3 (negatively), whereas 54.4% of the MS-EDSS-MSSS score was explained by the regression on age, IAI, homocysteine, folate, and CRP (all positively) and adiponectin, body mass index, and vitamin D3 (all negatively), female sex and the MTHFR 677 TT genotype. In patients and controls, 16.6% of the variance in the homocysteine was explained by the MTHFR 677 TT genotype and age (both positively), folate (negatively) and male sex. In conclusion, the MTHFR 677C>T variant was not directly associated with MS, disability, and disability progression; however, the TT genotype showed indirect effects on MS susceptibility and disability mediated by homocysteine.