A plasma proteomics method reveals links between ischemic stroke and MTHFR C677T genotype

Abstract

Methylene Tetrahydrofolate Reductase (MTHFR) catalyzes the conversion of methylene tetrahydrofolate to methylte trahydrofolate. The 677th nucleotide of the MTHFR gene is often regarded as a risk factor of cardiovascular disease. Previous studies demonstrated an elevated risk of ischemic stroke with the MTHFR677TT genotype. In this study, we employed a plasma proteomics method to investigate the connection between the polymorphism of the target nucleotide and stroke. In total, 28 protein spots were differentially expressed between the two groups, and of which, 25 protein spots were up-regulated and 3 were down-regulated. Five randomly selected spots were successfully identified as Haptoglobin (HPT) and Transferrin (TRFE). A functional analysis indicated that most of the differential expressed proteins (DEPs) were related to the inflammatory immune response. A Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that these DEPs were involved in the complement cascade reaction. Meanwhile, protein-protein interactions (PPIs) analysis highlighted the novel association between the C677T MTHFR genotype and Vitamin D binding protein (DBP), which was confirmed by a molecular genetic analysis. The results suggested that the phenotype of the MTHFR might be associated with multiple proteins that have a synergistic effect, which might be related to the mechanism of ischemic stroke.

Epigenetic regulation of inflammation in stroke

“…78 In addition, methylenetetrahydrofolate reductase (MHTFR) has also been implicated to trigger inflammatory responses and thereby is correlated with increased stroke risk. 79 MHTFR is an enzyme responsible for the catalytic regeneration of methionine, which eventually is required as a methyl donor for DNA methylation. 80 For many years, it has been widely investigated that individuals exhibiting polymorphism of C677 > T demonstrate hyperhomocysteinemia, a condition characterized by accumulation of homocysteine, a product formed following DNA methylation.…”

The Role of DNA Methylation in Stroke Recovery

“…Furthermore, methylenetetrahydrofolate reductase (MTHFR) is involved in initiating inflammatory reactions and is, therefore, associated with an elevated risk of stroke [ 7 , 73 ]. Methionine is a methyl donor for DNA methylation, and MTHFR is an important enzyme in Hcy metabolism that catalyzes the regeneration of methionine [ 74 ].…”

Minor Changes for a Major Impact: A Review of Epigenetic Modifications in Cell-Based Therapies for Stroke

“…A major player in these epigenetic responses and potential therapeutic target is DNA methyltransferases (DNMTs), which lead to immunosuppression in stroke [ 43 ], may be involved in cell death [ 44 ], and can even contribute to atherosclerosis as discussed above [ 45 ]. Another methylation modulator is methylenetetrahydrofolate reductase (MHTFR) [ 46 ], but its role in stroke risk and inflammation is debated.…”