Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C->T polymorphism.
BACKGROUND
Meta-analyses predict that a 25% lowering of plasma homocysteine would reduce the risk of coronary heart disease by 11% to 16% and stroke by 19% to 24%. Individuals homozygous for the methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism have reduced MTHFR enzyme activity resulting from the inappropriate loss of the riboflavin cofactor, but it is unknown whether their typically high homocysteine levels are responsive to improved riboflavin status.


RESULTS
From a register of 680 healthy adults 18 to 65 years of age of known MTHFR 677C-->T genotype, we identified 35 with the homozygous (TT) genotype and age-matched individuals with heterozygous (CT, n=26) or wild-type (CC, n=28) genotypes to participate in an intervention in which participants were randomized by genotype group to receive 1.6 mg/d riboflavin or placebo for a 12-week period. Supplementation increased riboflavin status to the same extent in all genotype groups (8% to 12% response in erythrocyte glutathione reductase activation coefficient; P<0.01 in each case). However, homocysteine responded only in the TT group, with levels decreasing by as much as 22% overall (from 16.1+/-1.5 to 12.5+/-0.8 micromol/L; P=0.003; n=32) and markedly so (by 40%) in those with lower riboflavin status at baseline (from 22.0+/-2.9 and 13.2+/-1.0 micromol/L; P=0.010; n=16). No homocysteine response was observed in the CC or CT groups despite being preselected for suboptimal riboflavin status.


CONCLUSIONS
Although previously overlooked, homocysteine is highly responsive to riboflavin, specifically in individuals with the MTHFR 677 TT genotype. Our findings might explain why this common polymorphism carries an increased risk of coronary heart disease in Europe but not in North America, where riboflavin fortification has existed for >50 years.
McNulty
Helene
H
Northern Ireland Centre for Food and Health, School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland. h.mcnulty@ulster.ac.uk
Dowey
Le Roy C
le RC
Strain
J J
JJ
Dunne
Adrian
A
Ward
Mary
M
Molloy
Anne M
AM
McAnena
Liadhan B
LB
Hughes
Joan P
JP
Hannon-Fletcher
Mary
M
Scott
John M
JM
D000293:Adolescent; D000328:Adult; D000368:Aged; D003327:Coronary Disease / Q000208:ethnology / Q000235:genetics / Q000517:prevention & control; D019587:Dietary Supplements; D004341:Drug Evaluation; D005060:Europe / Q000453:epidemiology; D006710:Homocysteine / Q000097:blood* / Q000187:drug effects; D006720:Homozygote; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D009656:North America / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide; D012256:Riboflavin / Q000494:pharmacology* / Q000627:therapeutic use
D006710:Homocysteine; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D012256:Riboflavin