Synergy between 677 TT MTHFR genotype and related folate SNPs regulates homocysteine level

Within the 677 TT MTHFR genotype, exhibited by 10% to 20% of the population, the combined number of mutant alleles contained within 4 other folate-related single nucleotide polymorphisms (1298A→C-MTHFR; 80G→A-RFC; 2756A→G-MS; 66A→G-MSR) appears to determine the balance between Hcy transsulfuration and folate-related Hcy remethylation. Significance level (P), as well as direction and strength (rs) of any associations, indicates that as combined number of folate-related mutations within 677TT MTHFR increases, so Hcy drops (P = .0035, rs = −0.54), whereas various folate indices increase (plasma folate P = .0019, rs = +0.57), as do glutathione (GSH) measurements. This suggests that an increase in the combined number of mutations within 677TT MTHFR is beneficial. As Hcy can be remethylated to methionine via folate metabolism, or transsulfurated to cysteine (Cys) leading to formation of GSH, we examined the 2 ratios: “GSH as a proportion of Hcy” and “plasma folate as a proportion of Hcy”. Both indices showed a significant positive correlation with number of folate mutations within TT genotype. Thus, Hcy transsulfuration seems to be positively selected within 677TT MTHFR as the number of related folate mutations increases. Findings are supported by 1-way analysis of variance which was used to assess differences in metabolite levels between the number (3 or less, 4, 5, 6, or more) of related mutant alleles within the 677 TT MTHFR genotype. With the exception of cysteine and GSH, the variance is not equally distributed between the number of folate-related mutant alleles within the TT genotype (P < .05). We conclude that there is an interactive effect of 1298A→C-MTHFR, 80G→A-RFC, 2756A→G-MS, and 66A→G-MSR within 677TT MTHFR genotype. The net effect of this interaction is to influence metabolic disposition of Hcy and therefore GSH, both of which are important determinants of disease risk.