Genetic polymorphisms of the folate pathway in amyotrophic lateral sclerosis and multiple sclerosis: a systematic review and meta-analysis

The folate cycle is a biochemical pathway that plays an important role in the development and maintenance of the nervous system. Biocompounds synthesized in this cycle must be carefully regulated, since the accumulation of some substances can be neurotoxic and increase susceptibility to neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). The methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate-homocysteine S-methyltransferase (MTR), and solute carrier family 19 member 1 (SLC19A1) genes encode important proteins for this regulation. In this systematic review and meta-analysis, we investigated the association of some polymorphisms in the MTHFR, MTR, and SLC19A1 genes and their associations with ALS and MS. The protocol of this systematic review is registered in the PROSPERO platform (CRD42021232352). We performed a search in EMBASE, Pubmed/NCBI, Scopus, Virtual Health Library (BVS), and Web of Science databases for studies that described polymorphisms in these genes, regardless of statistical association. Thirteen studies were included, and four polymorphisms were identified: C677T (rs1801133) and A1298C (rs1801131) in the MTHFR gene, A2756G (rs1805087) in the MTR gene, and A80G in the SLC19A1 gene. In the meta- analysis, the allelic and genotypic comparison for the C677T polymorphism showed a 1.5-fold increased risk for MS. Despite this significant result, we found a lack of association of most polymorphisms in the MTR, SLC19A1 and MTHFR genes and susceptibility for developing ALS and MS. Further studies are needed to clarify the role of polymorphisms in folate pathway genes in the susceptibility for developing these neurodegenerative diseases.

Automated summary

The folate cycle is crucial for the nervous system, with the MTHFR, MTR, and SLC19A1 genes playing important roles in its regulation. This study investigated the association of polymorphisms in these genes with ALS and MS, finding that the C677T polymorphism was associated with a 1.5-fold increased risk of MS. However, most polymorphisms were not associated with ALS and MS susceptibility. Further research is needed to understand the role of folate pathway gene polymorphisms in these neurodegenerative diseases.