Dr. Ron’s Research Review – November 20, 2013

© 2013

This week’s research review focuses on riboflavin and the MTHFR-TT polymorphism.

The homozygous mutant (TT) genotype produces an MTHFR enzyme with decreased activity and has a reported frequency of 10% worldwide, ranging from 4% to 18% in the United States, 20% in Northern China, and to as high as 32% in Mexico. (Wilson, Ward et al. 2012)

Vitamin B2 (riboflavin), in the coenzyme form FAD, is required as a cofactor for MTHFR and the decreased enzyme activity evident in individuals with the TT genotype results from the loss of its riboflavin cofactor. (Wilson, Ward et al. 2012)

Supplementation with riboflavin appears to stabilize the variant enzyme in vivo. (McNulty, Dowey le et al. 2006)

In those with the MTHFR-TT polymorphism, riboflavin (1.6 mg/d for 16 wk) produced an overall decrease in systolic (-9.2 ± 12.8 mm Hg; P = 0.001) and diastolic (-6.0 ± 9.9 mm Hg; P = 0.003) blood pressure. (Wilson, Ward et al. 2012)

Another study found that in those with the MTHFR-TT polymorphism, riboflavin (1.6 mg/d for 12 wk) decreased homocysteine by as much as 22% overall (from 16.1ӿÜ1.5 to 12.5ӿÜ0.8 ӿßmol/L; PӿÞ0.003; nӿÞ32) and markedly so (by 40%) in those with lower riboflavin status at baseline (from 22.0ӿÜ2.9 and 13.2ӿÜ1.0 ӿßmol/L; PӿÞ0.010; nӿÞ16). (McNulty, Dowey le et al. 2006)

Dr. Ron


Articles

Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C->T polymorphism

         (McNulty, Dowey le et al. 2006) Download

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. METHODS AND 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.


Riboflavin offers a targeted strategy for managing hypertension in patients with the MTHFR 677TT genotype: a 4-y follow-up

         (Wilson, Ward et al. 2012) Download

BACKGROUND: We recently reported that the elevated blood pressure (BP) observed in patients with cardiovascular disease who are homozygous for the 677C-->T polymorphism (TT genotype) in the gene encoding methylenetetrahydrofolate reductase (MTHFR) was responsive to supplementation with riboflavin-the cofactor for MTHFR. OBJECTIVE: The objective was to investigate the effect of riboflavin on BP targeted at patients with the TT genotype 4 y after initial investigation, during which time major changes in the clinical guidelines for antihypertensive therapy were introduced. DESIGN: A total of 83 patients (representing all 3 genotypes) who participated in a placebo-controlled riboflavin intervention for 16 wk in 2004 agreed to take part. Nested within this follow-up, those with the TT genotype (n = 31) proceeded to intervention with riboflavin (1.6 mg/d for 16 wk) or placebo, conducted in a crossover style whereby the 2004 treatment groups were reversed. RESULTS: At follow-up in 2008, as in 2004, patients with the TT genotype had higher systolic BP (P < 0.01), with a nonsignificant trend noted for higher diastolic BP (P = 0.051). Despite the marked changes in antihypertensive therapy that had occurred, BP remained unchanged in patients with the TT genotype at the time of follow-up. Riboflavin supplementation (administered in 2004 and 2008) produced an overall decrease in systolic (-9.2 +/- 12.8 mm Hg; P = 0.001) and diastolic (-6.0 +/- 9.9 mm Hg; P = 0.003) BP. CONCLUSIONS: Optimizing riboflavin status offers a low-cost targeted strategy for managing elevated BP in this genetically at-risk group. These findings, if confirmed in the general population, could have important implications for the prevention of hypertension.


Blood pressure in treated hypertensive individuals with the MTHFR 677TT genotype is responsive to intervention with riboflavin: findings of a targeted randomized trial

         (Wilson, McNulty et al. 2013) Download

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. The aim of this randomized trial, therefore, was to investigate the responsiveness of BP to riboflavin supplementation in hypertensive individuals with the TT genotype but without overt cardiovascular disease. From an available sample of 1427 patients with hypertension, we identified 157 with the MTHFR 677TT genotype, 91 of whom agreed to participate in the trial. Participants were stratified by systolic BP and randomized to receive placebo or riboflavin (1.6 mg/d) for 16 weeks. At baseline, despite being prescribed multiple classes of antihypertensive drugs, >60% of participants with this genotype had failed to reach goal BP (</=140/90 mm Hg). A significant improvement in the biomarker status of riboflavin was observed in response to intervention (P<0.001). Correspondingly, an overall treatment effect of 5.6+/-2.6 mm Hg (P=0.033) in systolic BP was observed, with pre- and postintervention values of 141.8+/-2.9 and 137.1+/-3.0 mm Hg (treatment group) and 143.5+/-3.0 and 144.3+/-3.1 mm Hg (placebo group), whereas the treatment effect in diastolic BP was not significant (P=0.291). In conclusion, these results show that riboflavin supplementation targeted at hypertensive individuals with the MTHFR 677TT genotype can decrease BP more effectively than treatment with current antihypertensive drugs only and indicate the potential for a personalized approach to the management of hypertension in this genetically at-risk group. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: ISRCTN23620802.


References

McNulty, H., R. C. Dowey le, et al. (2006). "Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C->T polymorphism." Circulation 113(1): 74-80. [PMID: 16380544]

Wilson, C. P., H. McNulty, et al. (2013). "Blood pressure in treated hypertensive individuals with the MTHFR 677TT genotype is responsive to intervention with riboflavin: findings of a targeted randomized trial." Hypertension 61(6): 1302-8. [PMID: 23608654]

Wilson, C. P., M. Ward, et al. (2012). "Riboflavin offers a targeted strategy for managing hypertension in patients with the MTHFR 677TT genotype: a 4-y follow-up." Am J Clin Nutr 95(3): 766-72. [PMID: 22277556]