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) 677C3 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. Methods and Results-From a register of 680 healthy adults 18 to 65 years of age of known MTHFR 677C3 T genotype, we identified 35 with the homozygous (TT) genotype and age-matched individuals with heterozygous (CT, nϭ26) or wild-type (CC, nϭ28) 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; PϽ0.01 in each case). However, homocysteine responded only in the TT group, with levels decreasing by as much as 22% overall (from 16.1Ϯ1.5 to 12.5Ϯ0.8 mol/L; Pϭ0.003; nϭ32) and markedly so (by 40%) in those with lower riboflavin status at baseline (from 22.0Ϯ2.9 and 13.2Ϯ1.0 mol/L; Pϭ0.010; nϭ16). 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 Ͼ50 years.

The frequency of the homozygous mutant MTHFR 677TT genotype is reported to be 10% worldwide, ranging from 4% to 18% in the United States, 20% in northern China to as high as 32% in Mexico. 12 The MTHFR enzyme catalyzes the conversion of 5, 10-methylenetetrahydrofolate into 5-methyltetrahydrofolate which, in turn, is required for the remethylation of homocysteine to methionine. The common 677C→T variant in MTHFR results in a thermolabile enzyme with decreased activity, typically leading to elevated plasma homocysteine in vivo. 13 Molecular studies demonstrate that the decreased activity of the variant enzyme is attributable to the loss of its riboflavin (ie, FAD; flavin adenine dinucleotide) Abstract-Intervention with riboflavin was recently shown to produce genotype-specific lowering of blood pressure (BP) in patients with premature cardiovascular disease homozygous for the 677C→T polymorphism (TT genotype) in the gene encoding the enzyme methylenetetrahydrofolate reductase (MTHFR). Whether this effect is confined to patients with high-risk cardiovascular disease is unknown.

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 677C3 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-analysis 2 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 supopulations 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. DisclosuresNone. Helene

Background:Women have an increased risk of iron deficiency during pregnancy because of the demands of the developing fetus. Iron supplements are commonly advocated as a prophylactic treatment and are generally taken with meals to reduce side effects, but iron can interfere with the absorption of zinc. Objective: The aim was to determine the effect of consuming an iron supplement (100 mg Fe/d as ferrous gluconate) with meals from 16 wk gestation to term on zinc status and absorption. Design: Stable-isotope techniques were used to measure zinc status (exchangeable zinc pool, EZP) and fractional zinc absorption (FZA) in early and late pregnancy from a meal consumed at a different time from that of iron supplement or placebo consumption in 6 women given iron supplements and 7 given a placebo. Results: FZA increased during pregnancy, independent of iron supplementation. FZA was significantly higher (P 0.001) at week 34 than at weeks 16 and 24, and urinary zinc excretion was higher at week 34 than at week 16 (P ҃ 0.02). The size of the EZP remained unchanged throughout pregnancy and was unaffected by iron supplementation. The iron status of iron-supplemented women was higher than that of the placebo group. Conclusions: In iron-replete pregnant women who consumed a Western diet, no detectable adverse effects on zinc metabolism were observed after ingestion of 100 mg Fe/d. An increase in the efficiency of zinc absorption was observed during late pregnancy.Am J Clin Nutr 2007;85:131-6.