The Relationship between Riboflavin and Plasma Total Homocysteine in the Framingham Offspring Cohort Is Influenced by Folate Status and the C677T Transition in the Methylenetetrahydrofolate Reductase Gene

Abstract

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate, the methyl donor for remethylation of homocysteine to methionine. The C677T MTHFR polymorphism is associated with mild hyperhomocysteinemia, but only in the presence of low folate status. Because MTHFR contains flavin adenine dinucleotide (FAD) as a prosthetic group, riboflavin status may also influence homocysteine metabolism. The objective of this study was to examine the association between riboflavin status and fasting plasma total homocysteine (tHcy) concentration while also considering MTHFR C677T genotype and folate status. The study was conducted using fasting plasma samples (n = 450) from the fifth examination of the Framingham Offspring Study cohort. All persons with the TT genotype and age- and sex-matched sets of individuals with the CT and CC genotypes were selected for determination of plasma riboflavin and flavin mono- and dinucleotide levels. Plasma riboflavin was associated with tHcy concentrations, but the association was largely confined to persons with plasma folate <12.5 nmol/L and TT genotype. In these persons, the mean tHcy among individuals with riboflavin levels <6.89 nmol/L was 14.5 micromol/L, whereas the mean tHcy for those with riboflavin > or = 11 nmol/L was 11.6 micromol/L (P-trend <0.03). Plasma flavin nucleotides were unrelated to tHcy concentrations. Our data suggest that riboflavin status may affect homocysteine metabolism, but only in a small segment of the population who have both low folate status and are homozygotes for the MTHFR C677T mutation.

Changes in lifestyle and total homocysteine in relation to MTHFR(C677T) genotype: the Inter99 study

“…On the other hand, this MTHFR genotype dependence could also be supportive of increased supplement use during follow-up as discussed above, as B vitamins are known to have a tHcy lowering effect especially in TT individuals (Jacques et al, 1996;Hustad et al, 2000;Jacques et al, 2002).…”

“…Whether an altered lifestyle and changes in lifestyle-related factors are associated with changes in tHcy have not been thoroughly investigated. The thermolabile variant of the methylenetetrahydrofolate reductase (MTHFR(C677T)) (Frosst et al, 1995), a regulating enzyme in tHcy metabolism, has been shown to modify the relation between several lifestyle factors and tHcy (Jacques et al, 1996;Hustad et al, 2000;Jacques et al, 2002;Husemoen et al, 2004). Thus the effect on tHcy of changes in lifestyle related factors may depend on MTHFR(C677T) genotype.…”

Effects of the interaction between the C677T 5,10-methylenetetrahydrofolate reductase polymorphism and serum B vitamins on homocysteine levels in pregnant women

“…An earlier animal study showed a significant association between vitamin B 2 and MTHFR that the enzyme activity and the relative amounts of 5-methyl THF were reduced in the liver of riboflavin-deficient rats (Bates & Fuller, 1986). Hustad et al (2000), McNulty et al (2002), and Jacques et al (2002) demonstrated that plasma vitamin B 2 was an independent determinant of plasma homocysteine, and this inverse dose-response relation was essentially confined to subjects with the C/T or T/T genotype of the MTHFR C677T polymorphism where the requirement of FAD for maximal catalytic activity might be increased (Hustad et al, 2000;Ueland et al, 2001). Several investigators have suggested that vitamin B 6 deficiency may lead to hyperhomocysteinemia, which is an established risk factor for adverse pregnancy outcome (van den Berg et al, 1994;Leeda et al, 1998).…”

Effect of lifestyle factors on plasma total homocysteine concentrations in relation to MTHFR(C677T) genotype. Inter99 (7)

“…Several studies have showed that B-vitamin status is a major determinant of tHcy in the general population (Jacques et al, 1996b(Jacques et al, , 2002Hustad et al, 2000;Moat et al, 2003). Little attention has been given to the effect of overall dietary pattern regarding tHcy.…”

“…Persons homozygous for the mutant T-allele have higher tHcy concentrations than persons with CC and CT genotypes (Husemoen et al, 2003). Moreover, the MTHFR(C677T) polymorphism has been shown to modify the relation between B-vitamin intake and tHcy (Jacques et al, 1996a(Jacques et al, , 2002Hustad et al, 2000). Suboptimal vitamin status is associated with much higher tHcy concentrations in persons with the TT genotype than in persons with the CC or CT genotypes.…”