Elsevier

Molecular Aspects of Medicine

Volume 53, February 2017, Pages 2-9
Molecular Aspects of Medicine

Review
Riboflavin, MTHFR genotype and blood pressure: A personalized approach to prevention and treatment of hypertension

https://doi.org/10.1016/j.mam.2016.10.002Get rights and content

Abstract

Hypertension is the leading risk factor contributing to mortality worldwide, primarily from cardiovascular disease (CVD), while effective treatment of hypertension is proven to reduce CVD events. Along with the well recognized nutrition and lifestyle determinants, genetic factors are implicated in the development and progression of hypertension. In recent years genome-wide association studies have identified a region near the gene encoding the folate-metabolizing enzyme methylenetetrahydrofolate reductase (MTHFR) among eight loci associated with blood pressure. Epidemiological studies, which provide a separate line of evidence to link this gene with blood pressure, show that the 677C→T polymorphism in MTHFR increases the risk of hypertension by 24–87% and CVD by up to 40%, albeit with a large geographical variation in the extent of excess disease risk suggestive of a gene–environment interaction. Emerging evidence indicates that the relevant environmental factor may be riboflavin, the MTHFR co-factor, via a novel and genotype-specific effect on blood pressure. Randomized trials conducted in hypertensive patients (with and without overt CVD) pre-screened for this polymorphism show that targeted riboflavin supplementation in homozygous individuals (MTHFR 677TT genotype) lowers systolic blood pressure by 6 to 13 mmHg, independently of the effect of antihypertensive drugs. The latest evidence, that the blood pressure phenotype associated with this polymorphism is modifiable by riboflavin, has important clinical and public health implications. For hypertensive patients, riboflavin supplementation can offer a non-drug treatment to effectively lower blood pressure in those identified with the MTHFR 677TT genotype. For sub-populations worldwide with this genotype, better riboflavin status may prevent or delay the development of high blood pressure. Thus riboflavin, targeted at those homozygous for a common polymorphism in MTHFR, may offer a personalized treatment or preventative strategy for hypertension. Further investigations of this novel gene–nutrient interaction in relation to blood pressure, hypertension and hypertension in pregnancy are required.

Introduction

Hypertension is the leading risk factor contributing to cardiovascular disease (CVD) and to mortality worldwide, while interventions to lower blood pressure, even by small amounts, are proven to decrease cardiovascular risk (World Health Organization, 2013, Mozaffarian et al, 2016). Multiple lifestyle and genetic factors are thought to contribute to the development and progression of hypertension, and there have been recent calls for more individual-focused approaches to lower blood pressure and thus improve cardiovascular health (Mozaffarian et al., 2016). Evidence from both GWAS and epidemiological studies implicates the gene encoding the folate-metabolizing enzyme methylenetetrahydrofolate reductase (MTHFR) in hypertension (Ehret et al, 2011, Yang et al, 2014a). Notably, the common 677C→T polymorphism in MTHFR is associated with an increased risk of not only hypertension (Yang et al., 2014a), but also CVD especially stroke (Holmes et al., 2011). The geographical variability in the extent of excess cardiovascular risk owing to this polymorphism points to a gene–environment interaction, and recent evidence suggests that riboflavin, the MTHFR co-factor (as FAD), may play an important modulating role in this relationship via a novel effect on blood pressure. This review will explore the available evidence that the under-recognized blood pressure phenotype associated with the MTHFR 677C→T polymorphism is modifiable by riboflavin status and the potential mechanisms that may explain this gene–nutrient interactive effect. The public health implications, and the translation of this novel role of riboflavin to healthcare will also be considered.

Section snippets

The burden of high blood pressure

Hypertension, defined as a systolic/diastolic blood pressure of 140/90 mmHg or greater, affects an estimated 1 billion people globally (World Health Organization, 2013). It is the leading risk factor contributing to mortality worldwide and accounts for over 9 million deaths annually, primarily from cardiovascular disease (CVD) (Lim et al., 2012). It is estimated that there is a doubling in the risk of cardiovascular diseases for each 20 mmHg rise in systolic blood pressure, or 10 mmHg rise in

Genetic studies

One-carbon metabolism has been linked with CVD, though not necessarily blood pressure, in numerous epidemiological studies. Most relevant studies in this area have focused on homocysteine as the putative cardiovascular risk factor, including those investigating the role of the 677C→T variant in the gene encoding the folate-metabolizing enzyme methylenetetrahydrofolate reductase (MTHFR), the most important genetic determinant of homocysteine in the general population. MTHFR is required for the

Riboflavin, one-carbon metabolism and blood pressure

The large geographical variability in the extent of excess cardiovascular risk owing to this polymorphism points to a gene–environment interaction. Folate only was previously considered as the relevant factor. Recent evidence suggests however that riboflavin, the MTHFR co-factor, may be the important modulating factor (at least in folate replete populations) via a novel effect on blood pressure.

Prevention and treatment of hypertension

Riboflavin, targeted at patients or adults generally with the relevant genotype, may offer a personalized non-drug approach for managing hypertension, with important clinical and public health implications. A decrease in systolic blood pressure by as little as 2 mmHg can decrease cardiovascular risk by as much as 10% (Lewington et al., 2002). Riboflavin was shown to lower blood pressure by 6–13 mmHg in patients identified with MTHFR 677TT genotype in the aforementioned trials (Horigan et al,

Conclusion and future perspectives

Supplemental riboflavin offers a personalized approach for managing blood pressure in genetically at-risk adults that aligns with the AHA strategy of targeting treatments at the individual level to improve cardiovascular health. Although genetic factors are well recognized to play a role in the development of hypertension, the MTHFR 677TT genotype is the only specific genetic factor linked with hypertension that provides a personalized management option. Neither the genetic predisposition to

Funding

The research described in this review was supported in part by: governmental funding from the Irish Department of Agriculture, Food and the Marine and Health Research Board (under the Food Institutional Research Measure, FIRM, initiative) and from the Northern Ireland Department for Employment and Learning (under its Strengthening the All-Ireland research base initiative); and from DSM Nutritional Products (funding for post-doctoral research post for CF Hughes received). None of these entities

Acknowledgements

This review article is dedicated to the memory of John M Scott.

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