ReviewRiboflavin, MTHFR genotype and blood pressure: A personalized approach to prevention and treatment of hypertension
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.
References (72)
Stratified, personalised or P4 medicine: a new direction for placing the patient at the centre of healthcare and health education
- et al.
Polymorphisms of genes involved in homocysteine metabolism in preeclampsia and in uncomplicated pregnancies
Eur. J. Obstet. Gynecol. Reprod. Biol
(2005) - et al.
5-Methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels: effects on vascular tetrahydrobiopterin availability and eNOS coupling
Circulation
(2006) - et al.
MTHFR 677 C>T Polymorphism reveals functional importance for 5-methyltetrahydrofolate, not homocysteine, in regulation of vascular redox state and endothelial function in human atherosclerosis
Circulation
(2009) - et al.
A clinical trial of the effects of dietary patterns on blood pressure DASH Collaborative Research Group
New Engl. J. Med
(1997) - et al.
Effects of comprehensive lifestyle modification on blood pressure control: main results of the PREMIER clinical trial
JAMA
(2003) - et al.
A common mutation in the methylenetetrahydrofolate reductase gene is associated with an accumulation of formylated tetrahydrofolates in red blood cells
Proc. Nat. Acad. Sci
(1998) - et al.
Biomarkers of nutrition for development – folate review
J. Nutr
(2015) - et al.
Personalised medicine in Canada: a survey of adoption and practice in oncology, cardiology and family practice
BMJ Open
(2011) - et al.
Homocysteine and stroke: evidence on a causal link from Mendelian randomisation
Lancet
(2005)
Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias
PLoS Med
Synthesis and recycling of tetrahydrobiopterin in endothelial function and vascular disease
Nitric Oxide
Quantitative regulation of intracellular endothelial nitric-oxide synthase (eNOS) coupling by both tetrahydrobiopterin-eNOS stoichiometry and biopterin redox status: insights from cells with tetregulated GTP cyclohydrolase I expression
J. Biol. Chem
Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk
Nature
Hypertension management in England: a serial cross-sectional study from 1994 to 2011
Lancet
An insight into the public acceptance of nutrigenomic-based personalised nutrition
Nutr. Res. Rev
Identifying multiple causative genes at a single GWAS locus
Genome Res
A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase
Nat. Genet
The global cost of nonoptimal blood pressure
J. Hypertens
The future direction of personalised nutrition: my diet, my phenotype, my genes
Proc. Nutr. Soc
The structure and properties of methylenetetrahydrofolate reductase from Escherichia coli suggest how folate ameliorates human hyperhomocysteinemia
Nat. Struct. Biol
The path to personalized medicine
NEJM
Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials
Lancet
Homocysteine and risk of ischemic heart disease and stroke
JAMA
Riboflavin lowers blood pressure in cardiovascular disease patients homozygous for the 677C>T polymorphism in MTHFR
J Hypertens
The methylenetetrahydrofolate reductase 677C→T polymorphism as a modulator of a B vitamin network with major effects on homocysteine metabolism
Am. J. Hum. Genet
Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations
Circulation
MTHFR C677T polymorphism and risk of coronary heart disease: a meta-analysis
JAMA
Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension
J. Clin. Invest
Efficacy of homocysteine-lowering therapy with folic acid in stroke prevention: a meta-analysis
Stroke
Genome-wide association study of blood pressure and hypertension
Nat. Genet
Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies
Lancet
Meta-analysis of the MTHFR 677C→T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventative potential of folate
Br. Med. J.
A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010
Lancet
Academic family physicians’ perception of genetic testing and integration into practice: a CERA study
Fam. Med
Riboflavin status, MTHFR genotype and blood pressure: current evidence and implications for personalised nutrition
Proc. Nutr. Soc
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