Genetic Variants in Folate Metabolism and Their Role in Multiple Sclerosis Risk
Multiple sclerosis (MS) is a complex, chronic inflammatory disease of the central nervous system (CNS) with a multifaceted etiology. Researchers have long investigated the genetic and environmental factors contributing to the development and progression of MS. A recent study by Ali Erkan Aşcı, Gürdal Orhan, and Bensu Karahalil, published in Neurological Research, explores the role of genetic variants in folate metabolism and their association with MS risk. This study provides novel insights into the biochemical underpinnings of MS, particularly in the context of the Turkish population.
MS is characterized by the immune system attacking the myelin sheath, leading to neurological dysfunction. Despite extensive research, the exact cause of MS remains elusive. However, it is widely accepted that genetic predisposition, environmental triggers, and immunological responses play crucial roles. One area of interest is one-carbon metabolism, particularly the metabolism of folate, which is vital for DNA synthesis and repair, and methylation processes.
The primary aim of the study was to investigate the contribution of polymorphisms in the genes encoding key enzymes of folate metabolism—Methylenetetrahydrofolate Reductase (MTHFR), Methionine Synthase Reductase (MTRR), and Methionine Synthase (MTR)—to MS susceptibility. Additionally, the study measured levels of homocysteine (Hcy), cysteine (Cys), and vitamin B12 (VitB12) in the blood of MS patients and healthy controls.
A total of 147 MS patients and 127 healthy controls were enrolled. The gene polymorphisms were analyzed using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP), and plasma levels of Hcy, Cys, and VitB12 were measured by Enzyme-Linked Immunosorbent Assay (ELISA).
Key Findings
The study yielded several important findings:
Biochemical Differences: MS patients exhibited lower levels of Hcy and VitB12 and higher levels of Cys compared to healthy controls. This suggests that the methionine synthesis is impaired in MS, leading to an increased transsulfuration activity that converts Hcy to Cys.
Gene Polymorphisms and MS Risk:
No significant association was found between the MTHFR C677T, MTR A2756G, and MTRR A66G polymorphisms and MS risk.
The T allele of MTHFR C677T and the G allele of MTR A2756G were identified as risk factors for elevated serum Cys levels in MS patients.
The G allele of MTR A2756G was also associated with lower VitB12 levels in MS patients.
The study's findings highlight the complex interplay between genetic variants and biochemical cascades in MS. The observed biochemical alterations suggest that disruptions in folate metabolism may contribute to the pathophysiology of MS. Elevated Cys levels and reduced Hcy and VitB12 levels point to an impaired methionine synthesis, potentially exacerbating oxidative stress and neuroinflammation in MS.
The lack of a direct association between the studied gene polymorphisms and MS risk suggests that while these variants may influence biochemical parameters, their role in MS susceptibility might be modulated by other genetic or environmental factors.
Conclusions
This study is the first to investigate the interactive effects of MTHFR C677T, MTR A2756G, and MTRR A66G polymorphisms on Hcy, Cys, and VitB12 levels and their association with MS in a Turkish population. The findings suggest that therapeutic strategies aimed at correcting folate metabolism imbalances, such as folate or vitamin B12 supplementation, might hold promise in managing MS.
Future Directions
Further research is needed to elucidate the precise mechanisms by which folate metabolism influences MS pathogenesis and to explore the potential therapeutic benefits of targeting these metabolic cascades. Additionally, larger, multicentric studies across diverse populations are essential to validate these findings and uncover the broader implications of folate metabolism in MS.
References
Aşcı, A. E., Orhan, G., & Karahalil, B. (2024). Genetic variants of folate metabolism and the risk of multiple sclerosis. Neurological Research, 46(6), 544-552. doi:10.1080/01616412.2024.2337519
