Response to Letter Regarding Article, “Riboflavin Lowers Homocysteine in Individuals Homozygous for the MTHFR 677C→T Polymorphism”
We thank Powers et al for their positive comments on our article.1 Their criticism is that our sample is not representative of the United Kingdom or European populations, and that our interpretation of the results in relation to food policy is therefore inappropriate.
The statement that statistical inference is compromised is misleading because it is very clear in our article that the inference is not being made about the general population, but rather a subpopulation, ie, people homozygous for the MTHFR 677C→T polymorphism (ie, TT genotype). To specifically investigate this subpopulation, we screened 680 healthy adults and identified just over 10% with the TT genotype; this is typical of populations worldwide. Powers et al have inappropriately compared homocysteine levels in our TT subpopulation with those found in the general UK population. The correct comparison is with other studies that report homocysteine levels in TT genotype subpopulations. Homocysteine values in one such meta-analysis2 were comparable with our data and were 25% higher in people with TT compared with CC (wild-type) genotypes; however, the extent of elevation varied considerably between studies,2 presumably because of differences in the prevailing status of folate and/or riboflavin. The elevated homocysteine in TT su-populations is generally far less marked within US compared with European populations where (unlike the United States) there is no exposure to mandatory fortification with folate or riboflavin. Correspondingly, this polymorphism carries an increased risk of cardiovascular disease in European populations but not in those in North America.3
We feel that our findings can contribute to the debate regarding food fortification with folate and related B-vitamins currently being considered by many governments. In our study,1 the marked homocysteine-lowering effect of riboflavin in people with the TT genotype was achieved with very low doses (1.6 mg/d, ie, recommended dietary level). If a sufficiently powered clinical trial proves that homocysteine is linked in a causative way to heart disease or stroke, then exposure of the general population to low-dose riboflavin through fortification (as in the United States) may offer a cheap, safe, and effective means of reducing disease risk among substantial subpopulations who carry the TT genotype and are unaware of it.
McNulty H, Dowey LC, Strain JJ, Dunne A, Ward M, Molloy AM, McAnena LB, Hughes JP, Hannon-Fletcher M, Scott JM. Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C→T polymorphism. Circulation. 2006; 113: 74–80.
Brattström L, Wilcken DEL, Ohrvik J, Brudin L. Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: the result of a meta-analysis. Circulation. 1998; 98: 2520–2526.