title: Riboflavin status modifies the effects of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) polymorphisms on homocysteine.
abstract: Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR), riboflavin-dependent enzymes, participate in homocysteine metabolism. Reported effects of riboflavin status on the association between the MTHFR 677C>T polymorphism and homocysteine vary, and the effects of the MTRR 66A>G or MTRR 524C>T polymorphisms on homocysteine are unclear. We tested the hypothesis that the effects of the MTHFR 677C>T, MTRR 66A>G and MTRR 524C>T polymorphisms on fasting plasma total homocysteine (tHcy) depend on riboflavin status (erythrocyte glutathionine reductase activation coefficient, optimum: <1.2; marginally deficient: 1.2-1.4; deficient: ≥1.4) in 771 adults aged 18-75 years. MTHFR 677T allele carriers with middle or low tertile plasma folate (<14.7 nmol/L) had 8.2 % higher tHcy compared to the 677CC genotype (p < 0.01). This effect was eliminated when riboflavin status was optimal (p for interaction: 0.048). In the lowest cobalamin quartile (≤273 pmol/L), riboflavin status modifies the relationship between the MTRR 66 A>G polymorphism and tHcy (p for interaction: 0.034). tHcy was 6.6 % higher in MTRR 66G allele carriers compared to the 66AA genotype with marginally deficient or optimal riboflavin status, but there was no difference when riboflavin status was deficient (p for interaction: 0.059). tHcy was 13.7 % higher in MTRR 524T allele carriers compared to the 524CC genotype when cobalamin status was low (p < 0.01), but no difference was observed when we stratified by riboflavin status. The effect of the MTHFR 677C>T polymorphism on tHcy depends on riboflavin status, that of the MTRR 66A>G polymorphism on cobalamin and riboflavin status and that of the MTRR 524C>T polymorphism on cobalamin status.
authors.affiliation: Area of Preventive Medicine and Public Health, Faculty of Medicine and Health Sciences, IISPV, Universitat Rovira i Virgili (URV), C/Sant Llorenç, 21, 43201, Reus, Spain.
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: García-Minguillán
authors.forename: Joan D
authors.initials: JD
authors.lastname: Fernandez-Ballart
authors.forename: Santiago
authors.initials: S
authors.lastname: Ceruelo
authors.forename: Lídia
authors.initials: L
authors.lastname: Ríos
authors.forename: Olalla
authors.initials: O
authors.lastname: Bueno
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Berrocal-Zaragoza
authors.forename: Anne M
authors.initials: AM
authors.lastname: Molloy
authors.forename: Per M
authors.initials: PM
authors.lastname: Ueland
authors.forename: Klaus
authors.initials: K
authors.lastname: Meyer
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Murphy