Published Online
on December 27, 2005

A more recent version of this article appeared on January 3, 2006

This Article Full Text (PDF) All Versions of this Article: 113/1/74    most recent CIRCULATIONAHA.105.580332v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by McNulty, H. Articles by Scott, J. M. Search for Related Content PubMed PubMed Citation Articles by McNulty, H. Articles by Scott, J. M. Related Collections Nutrition Primary prevention Primary and Secondary Stroke Prevention Risk Factors for Stroke Genetics of cardiovascular disease

Submitted on August 2, 2005
Revised on October 21, 2005
Accepted on October 31, 2005

Riboflavin Lowers Homocysteine in Individuals Homozygous for the MTHFR 677CT Polymorphism

Helene McNulty PhD^*, Le Roy C. Dowey PhD, J. J. Strain PhD, Adrian Dunne PhD, Mary Ward PhD, Anne M. Molloy PhD, Liadhan B. McAnena PhD, Joan P. Hughes MSc, Mary Hannon-Fletcher PhD, and John M. Scott ScD

From the Northern Ireland Centre for Food and Health, School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland (H.M., L.C.D., J.J.S., M.W., L.B.M., J.P.H., M.H.-F.); Department of Biochemistry, Trinity College Dublin, Dublin, Ireland (A.M.M., J.M.S.); and the Department of Statistics, University College Dublin, Dublin, Ireland (A.D.).

^* To whom correspondence should be addressed. E-mail: h.mcnulty{at}ulster.ac.uk.

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) 677CT 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.

Methods and Results--From a register of 680 healthy adults 18 to 65 years of age of known MTHFR 677CT 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 µmol/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 µmol/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.

Key words: cardiovascular diseases • homocysteine • methylenetetrahydrofolate reductase (NADPH2) • nutrition • riboflavin

This article has been cited by other articles:

				J. M. Wallace, M. P Bonham, J. Strain, E. M Duffy, P. J Robson, M. Ward, H. McNulty, P. W Davidson, G. J Myers, C. F Shamlaye, et al. Homocysteine concentration, related B vitamins, and betaine in pregnant women recruited to the Seychelles Child Development Study Am. J. Clinical Nutrition, February 1, 2008; 87(2): 391 - 397. [Abstract] [Full Text] [PDF]

				C. Solis, K. Veenema, A. A. Ivanov, S. Tran, R. Li, W. Wang, D. J. Moriarty, C. V. Maletz, and M. A. Caudill Folate Intake at RDA Levels Is Inadequate for Mexican American Men with the Methylenetetrahydrofolate Reductase 677TT Genotype J. Nutr., January 1, 2008; 138(1): 67 - 72. [Abstract] [Full Text] [PDF]

				L. Hoey, H. McNulty, N. Askin, A. Dunne, M. Ward, K. Pentieva, J. Strain, A. M Molloy, C. A Flynn, and J. M Scott Effect of a voluntary food fortification policy on folate, related B vitamin status, and homocysteine in healthy adults Am. J. Clinical Nutrition, November 1, 2007; 86(5): 1405 - 1413. [Abstract] [Full Text] [PDF]

				M. den Heijer, H. J. Blom, F. R. Rosendaal, and G. M. J. Bos Response: Homocysteine lowering and recurrent venous thrombosis: the VITRO trial Blood, June 15, 2007; 109(12): 5521 - 5522. [Full Text] [PDF]

				A. G. Tsamaloukas Vitamins and Thrombosis (VITRO) study--homocysteine lowering with B vitamins Blood, June 15, 2007; 109(12): 5520 - 5521. [Full Text] [PDF]

				H. J. Powers, I. F.W. McDowell, and S. J. Moat Letter by Powers et al Regarding Article, "Riboflavin Lowers Homocysteine in Individuals Homozygous for the MTHFR 677C->T Polymorphism" Circulation, July 25, 2006; 114(4): e65 - e65. [Full Text] [PDF]

				H. McNulty, L. R. C. Dowey, J.J. Strain, M. Ward, L. B. McAnena, J. P. Hughes, M. Hannon-Fletcher, A. Dunne, A. M. Molloy, and J. M. Scott Response to Letter Regarding Article, "Riboflavin Lowers Homocysteine in Individuals Homozygous for the MTHFR 677C->T Polymorphism" Circulation, July 25, 2006; 114(4): e66 - e66. [Full Text] [PDF]