The effects of the MTHFR 677C>T (rs1801133) genetic variant on susceptibility and disability worsening in multiple sclerosis patients are mediated by homocysteine.

Autor: Ribeiro CM; Postgraduate Program of Clinical and Laboratory Pathophysiology, Health Sciences Center, State University of Londrina, Londrina, Paraná, Brazil., Oliveira SR; Postgraduate Program of Clinical and Laboratory Pathophysiology, Health Sciences Center, State University of Londrina, Londrina, Paraná, Brazil; Department of Pathology, Clinical Analysis, and Toxicology, Health Sciences Center, State University of Londrina, Paraná, Brazil., Flauzino T; Experimental Pathology Postgraduate Program, Biological Sciences Center, State University of Londrina, Londrina, Paraná, Brazil., Alfieri DF; Department of Pharmaceutical Sciences, Health Sciences Center, State University of Londrina, Londrina, Paraná, Brazil., Simão ANC; Postgraduate Program of Clinical and Laboratory Pathophysiology, Health Sciences Center, State University of Londrina, Londrina, Paraná, Brazil; Department of Pathology, Clinical Analysis, and Toxicology, Health Sciences Center, State University of Londrina, Paraná, Brazil., Lozovoy MAB; Postgraduate Program of Clinical and Laboratory Pathophysiology, Health Sciences Center, State University of Londrina, Londrina, Paraná, Brazil; Department of Pathology, Clinical Analysis, and Toxicology, Health Sciences Center, State University of Londrina, Paraná, Brazil., Maes M; Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, PR China; Key Laboratory of Psychosomatic Medicine, Chinese Academy of Medical Sciences, Chengdu 610072, PR China., Reiche EMV; Postgraduate Program of Clinical and Laboratory Pathophysiology, Health Sciences Center, State University of Londrina, Londrina, Paraná, Brazil; Catholic Pontifical University, School of Medicine, Campus Londrina, Londrina, Paraná, Brazil. Electronic address: reiche@sercomtel.com.br.
Jazyk: angličtina
Zdroj: Multiple sclerosis and related disorders [Mult Scler Relat Disord] 2024 Nov; Vol. 91, pp. 105883. Date of Electronic Publication: 2024 Sep 08.
DOI: 10.1016/j.msard.2024.105883
Abstrakt: Background: Interactions between genetic and environmental variables contribute to the autoimmune inflammatory process in multiple sclerosis (MS). Elevated homocysteine levels, and vitamin D, vitamin B12, and folate deficiencies are some of the environmental factors associated with the pathogenesis of MS. Considering that the relationship between MTHFR 677C>T (rs1801133) genetic variant, homocysteine, and folate in patients with MS remains unclear and that their role were not extensively explored in the clinical course of the disease, we investigated whether this variant and plasma homocysteine and folate levels are associated with MS susceptibility, disability, disability progression, and inflammatory biomarkers.
Methods: The case-control study included 163 patients with MS categorized using the Expanded Disability Status Scale (EDSS) as mild (EDSS<3) and moderate/high (EDSS≥3) disability, and 226 healthy controls (HC). Disability progression was evaluated using Multiple Sclerosis Severity Score (MSSS) and the MTHFR 677C>T variant was genotyped using real time polymerase chain reaction. The plasma levels of some inflammatory biomarkers were determined. Two new composed scores were proposed: the first, namely as inflammatory activity index (IAI), was entered as a latent vector extracted from the macrophage M1 + T helper (Th)1 + Th17 + Th2 + T regulatory (Treg) cytokines, + tumor necrosis factor (TNF)-α+ soluble TNF receptor (sTNFR)-1 + sTNFR2. The second score, namely MS-severity index was entered as a latent vector extracted from the EDSS + MSSS scores + MS diagnosis.
Results: Patients with MS showed higher homocysteine and folate than controls (p < 0.001); homocysteine, and the M1, Th1, Th17, and Th2 Treg cytokine values were different between the three study groups and increased from HC to MS patients with mild disability and to MS patients with moderate/high disability (p < 0.0001). The levels of TNF-α and their soluble receptors sTNFR1 and sTNFR2 were higher in MS patients with EDSS≥3 than in the two other groups (EDSS<3 and HC) (p < 0.001). There was no association between the MTHFR 677 C > T genotypes and MS susceptibility, disability and disability progression (p > 0.05). Moreover, 21.8 % of the disability variance was explained by age, IAI and C-reactive protein (CRP) (all positively associated); 10.9 % of the disability progression variance was predicted by IAI and CRP (both positively) and 25-hydroxyvitamin D (negatively), whereas 54.4 % of the severity index (MS-EDSS-MSSS) was explained by the regression on age, IAI, homocysteine, folate, and CRP (all positively), and adiponectin, body mass index, and 25-hydroxyvitamin D (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.
Conclusion: The MTHFR 677C>T variant has an indirect effect on the increase in disability in patients with MS, which also depends on factors such as age, sex, ad folate status.
Competing Interests: Declaration of competing interest There is no conflict of interest to declare. None of the authors are involved in the publication process or have a financial or other beneficial interest in the products or concepts mentioned in the submitted manuscript.
(Copyright © 2024. Published by Elsevier B.V.)
Databáze: MEDLINE
Externí odkaz: