Riboflavin status, MTHFR genotype and blood pressure: current evidence and implications for personalised nutrition

Clinical deficiency of the B-vitamin riboflavin (vitamin B2) is largely confined to developing countries; however accumulating evidence indicates that suboptimal riboflavin status is a widespread problem across the developed world. Few international data are available on riboflavin status as measured by the functional biomarker, erythrocyte glutathione reductase activation coefficient, considered to be the gold standard index. One important role of riboflavin in the form of flavin dinucleotide is as a co-factor for the folate-metabolising enzyme methylenetetrahydrofolate reductase (MTHFR). Homozygosity for the common C677T polymorphism in MTHFR, affecting over 10 % of the UK and Irish populations and up to 32 % of other populations worldwide, has been associated with an increased risk of CVD, and more recently with hypertension. This review will explore available studies reporting riboflavin status worldwide, the interaction of riboflavin with theMTHFRC677T polymorphism and the potential role of riboflavin in personalised nutrition. Evidence is accumulating for a novel role of riboflavin as an important modulator of blood pressure (BP) specifically in individuals with theMTHFR677TT genotype, with results from a number of recent randomised controlled trials demonstrating that riboflavin supplementation can significantly reduce systolic BP by 5–13 mmHg in these genetically at risk adults. Studies are however required to investigate the BP-lowering effect of riboflavin in different populations and in response to doses higher than 1·6 mg/d. Furthermore, work focusing on the translation of this research to health professionals and patients is also required.

Download Full-text

Impact of the common MTHFR 677C→T polymorphism on blood pressure in adulthood and role of riboflavin in modifying the genetic risk of hypertension: evidence from the JINGO project

BMC Medicine ◽

10.1186/s12916-020-01780-x ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Mary Ward ◽

Catherine F. Hughes ◽

J. J. Strain ◽

Rosie Reilly ◽

Conal Cunningham ◽

...

Keyword(s):

Blood Pressure ◽

Genetic Risk ◽

Antihypertensive Treatment ◽

Methylenetetrahydrofolate Reductase ◽

Randomised Trial ◽

Population Based ◽

Nutrition Survey ◽

Increased Risk ◽

The Impact ◽

Riboflavin Status

Abstract Background Genome-wide and clinical studies have linked the 677C→T polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR) with hypertension, whilst limited evidence shows that intervention with riboflavin (i.e. the MTHFR co-factor) can lower blood pressure (BP) in hypertensive patients with the variant MTHFR 677TT genotype. We investigated the impact of this common polymorphism on BP throughout adulthood and hypothesised that riboflavin status would modulate the genetic risk of hypertension. Methods Observational data on 6076 adults of 18–102 years were drawn from the Joint Irish Nutrigenomics Organisation project, comprising the Trinity-Ulster Department of Agriculture (TUDA; volunteer sample) and the National Adult Nutrition Survey (NANS; population-based sample) cohorts. Participants were recruited from the Republic of Ireland and Northern Ireland (UK) in 2008–2012 using standardised methods. Results The variant MTHFR 677TT genotype was identified in 12% of adults. From 18 to 70 years, this genotype was associated with an increased risk of hypertension (i.e. systolic BP ≥ 140 and/or a diastolic BP ≥ 90 mmHg): odds ratio (OR) 1.42, 95% confidence interval (CI) 1.07 to 1.90; P = 0.016, after adjustment for antihypertensive drug use and other significant factors, namely, age, male sex, BMI, alcohol and total cholesterol. Low or deficient biomarker status of riboflavin (observed in 30.2% and 30.0% of participants, respectively) exacerbated the genetic risk of hypertension, with a 3-fold increased risk for the TT genotype in combination with deficient riboflavin status (OR 3.00, 95% CI, 1.34–6.68; P = 0.007) relative to the CC genotype combined with normal riboflavin status. Up to 65 years, we observed poorer BP control rates on antihypertensive treatment in participants with the TT genotype (30%) compared to those without this variant, CT (37%) and CC (45%) genotypes (P < 0.027). Conclusions The MTHFR 677TT genotype is associated with higher BP independently of homocysteine and predisposes adults to an increased risk of hypertension and poorer BP control with antihypertensive treatment, whilst better riboflavin status is associated with a reduced genetic risk. Riboflavin intervention may thus offer a personalised approach to prevent the onset of hypertension in adults with the TT genotype; however, this requires confirmation in a randomised trial in non-hypertensive adults.

Download Full-text

Investigation of Blood Pressure during the First Trimester of Pregnancy in relation to the MTHFR C677T Polymorphism

Proceedings of The Nutrition Society ◽

10.1017/s0029665120005340 ◽

2020 ◽

Vol 79 (OCE2) ◽

Author(s):

E. Psara ◽

E. O'Sullivan ◽

K. Pentieva ◽

M. Ward ◽

G. Horigan ◽

...

Keyword(s):

Blood Pressure ◽

Pregnant Women ◽

First Trimester ◽

Functional Assay ◽

C677t Polymorphism ◽

Genotype Group ◽

Lower Status ◽

Riboflavin Status ◽

In Pregnancy

AbstractThe common C677T polymorphism in the MTHFR gene encoding the folate-metabolising enzyme methylenetetrahydrofolate reductase is implicated in hypertension and hypertension in pregnancy. Hypertension affects up to 15% of all pregnancies and has been identified as a leading cause of maternal and neonatal morbidity and mortality worldwide. We previously reported higher systolic and diastolic blood pressure (BP) in non-pregnant women with the variant MTHFR 677TT genotype compared to CT/CC genotypes. In addition, randomised controlled trials (RCTs) in non-pregnant hypertensive adults from our Centre demonstrated that supplemental riboflavin (co-factor for MTHFR) lowers BP specifically in those with the TT genotype. However, the role of this common folate polymorphism and its interaction with riboflavin during pregnancy remains unclear. The aim of this study was to investigate the impact of MTHFR genotype and riboflavin status on BP in pregnancy. Data were generated from the ongoing Optimal Nutrition for the Prevention of Hypertension (OptiPREG) project. Pregnant women were recruited at the end of the first trimester from antenatal clinics in Northern Ireland and in the Republic of Ireland. Participants were screened for MTHFR genotype and BP was measured according to current clinical guidelines. Biomarker status of riboflavin was determined using the erythrocyte glutathione reductase activation coefficient (EGRac), a functional assay with higher EGRac values representing a lower status. Overall, 117 (11.6%) participants were identified with the variant MTHFR 677TT genotype. Both systolic and diastolic BP decreased from 8th to 16th gestational week (GW), however, this typical BP pattern was not observed in the TT genotype group. After adjusting for maternal age, GW and body mass index, women with the TT genotype at 12th GW had higher mean systolic (P 0.035) and diastolic (P 0.034) BP. When the results at the 12th GW were stratified by riboflavin status, the BP phenotype owing to this polymorphism was evident only among women with lower status (i.e. EGRac > 1.30), with mean (SEM) systolic BP of 120.4 (3.1) mmHg compared to 112.6 (2.5) mmHg in those with higher status (EGRac ≤ 1.30) within the TT genotype group; in contrast, low versus high riboflavin status had no impact on BP in CT/CC genotype groups. These results suggest that MTHFR genotype influences BP during pregnancy and that riboflavin can exert an important modulating effect on BP in women with TT genotype. An RCT is required to fully investigate the role of MTHFR genotype and its interactive effect with riboflavin in BP during pregnancy.

Download Full-text

Intakes and status of riboflavin in a representative sample of Irish adults aged 18–90 years screened for MTHFR C677T polymorphism

Proceedings of The Nutrition Society ◽

10.1017/s0029665120000191 ◽

2020 ◽

Vol 79 (OCE2) ◽

Author(s):

Emma O'Sullivan ◽

Laura Kehoe ◽

Janette Walton ◽

Helene McNulty ◽

Mary Ward ◽

...

Keyword(s):

Blood Pressure ◽

Dietary Intake ◽

Representative Sample ◽

Functional Assay ◽

C677t Polymorphism ◽

Increased Risk ◽

Significant Difference ◽

Nationally Representative ◽

The Impact ◽

Riboflavin Status

AbstractMeta-analyses of epidemiological data report that adults who carry a common polymorphism, the MTHFR 677C→T, in the gene encoding the folate-metabolising enzyme methylenetetrahydrofolate reductase (MTHFR) have a 40% increased risk of CVD and an 87% increased risk of hypertension. Riboflavin (vitamin B2), in its co-enzymatic form flavin adenine nucleotide (FAD), is required as a co-factor by MTHFR and previous trials in hypertensive patients have shown a blood pressure lowering response to riboflavin supplementation that is specific to individuals homozygous for this polymorphism (TT genotype). Low folate status is commonly reported in adults with the TT genotype however the effect of this genetic variant on riboflavin status has not previously been investigated. The aim of this study, therefore, was to investigate dietary intake and biomarker status of riboflavin by MTHFR genotype in Irish adults using data from the National Adult Nutrition Survey (2008–2010) (www.iuna.net).A 4-day semi-weighed food record was used to collect food and beverage intake data from a representative sample of 1500 Irish adults (18–90 years). Dietary intake data were analysed using WISP© based on UK food composition tables (modified to include recipes of composite dishes, nutritional supplements, fortified foods and generic Irish foods that were commonly consumed). Usual intakes were calculated via the NCI-method using SAS© Enterprise Guide. Blood samples (n = 1126) were collected by venepuncture by a trained professional and were processed and analysed using standard operating procedures. Biomarker status of riboflavin was determined by erthyrocyte gluthathione reductase activation coefficient (EGRac), a functional assay that measures the activity of the enzyme glutathione reductase before and after in vitro activation with its prosthetic group FAD; a lower value indicates better status.It was found that 12% of the population had the TT genotype. As expected, there was no significant difference in riboflavin intake across the genotype (CC, CT or TT) groups. Similarly, no significant genotype differences in riboflavin status (EGRac) were observed (1.36 vs 1.37 vs 1.38 respectively). Overall, 61% of the total population had EGRac values > 1.3, indicative of low/deficient status with no significant difference observed between the genotype groups (60%,61% and 61%, respectively).These data suggest that riboflavin status is not influenced by the C677T polymorphism in MTHFR in this cohort of nationally representative Irish adults. Further research is needed to see the impact of riboflavin status on blood pressure across the genotype groups in this nationally representative cohort of Irish adults.

Download Full-text

P3566Ambulatory blood pressure response to riboflavin supplementation in adults with the C677T polymorphism in the folate metabolising enzyme methylenetetrahydrofolate reductase (MTHFR)

European Heart Journal ◽

10.1093/eurheartj/ehz745.0428 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

M Ward ◽

C F Hughes ◽

A Mc Mahon ◽

M Rooney ◽

J J Strain ◽

...

Keyword(s):

Methylenetetrahydrofolate Reductase ◽

Blood Pressure Response ◽

P Value ◽

C677t Polymorphism ◽

Night Time ◽

Reliable Assessment ◽

Increased Risk ◽

Clinical Research Facility ◽

To Receive ◽

Riboflavin Status

Abstract Background Epidemiological evidence suggests that the C677T polymorphism in the folate metabolising enzyme MTHFR is associated with a 24–87% increased risk of hypertension. Riboflavin (a cofactor for MTHFR) can modify this phenotype, as demonstrated in a series of RCTs, at this centre. ABPM measures BP over 24hrs and provides a more reliable assessment of an individual's BP compared to clinic BP. Aim To investigate the effect of riboflavin supplementation on BP (by ABPM) in adults with the MTHFR 677TT genotype. Methods Adults (n=3462) were recruited and screened for the MTHFRTT genotype and those eligible (n=81), were stratified by baseline SBP and randomised to receive riboflavin (10mg/day/16weeks) or placebo. Riboflavin status was measured using the erythrocyte glutathione reductase activation coefficient (EGRac) assay and clinic and ABPM were measured in accordance with clinical guidelines. Results Mean 24hr, daytime and night-time SBP was 6mmHg higher (p<0.05) in adults with the TT v CC genotype. BP response to riboflavin was strongly dependent on baseline BP. In participants with a baseline SBP≥125mmHg, riboflavin resulted in a significant BP lowering in daytime SBP (Table). Day-time SBP response to riboflavin Treatment Placebo P-value Age 48.6 (11.3) 47.8 (12.0) 0.823 Male n (%) 17 (73.9) 12 (46.2) 0.093 BMI 28.8 (3.8) 27.2 (3.1) 0.131 Riboflavin status (EGRac)† Pre 1.33 (1.28–1.38) 1.29 (1.24–1.34) Post 1.20 (1.14–1.25) 1.31 (1.25–1.36) <0.001 Change −0.12 0.02 Daytime BP (mmHg)‡ Pre 137.1 (132.7–141.3) 134.7 (130.3–139.1) Post 133.0 (128.9–138.1) 134.8 (130.6–139.1) 0.036 Change −3.8 −0.2 ANCOVA, adjusting for sex. †Higher EGRac values indicate lower riboflavin status; ‡mean of participant daytime/awake hrs personalised for each participant. Conclusion This is the first study to show, using ABPM, that riboflavin supplementation, targeted at adults with the MTHFR 677TT genotype, results in significant lowering of mean, day and night BP. Given the frequency of this genotype worldwide (approximately 10%, but as high as 30% in some populations) these findings could offer a personalised approach for BP management in at-risk sub-populations. Acknowledgement/Funding This work was supported by DSM Nutritional Products, Ltd and Wellcome Trust-Wolfston Northern Ireland Clinical Research Facility are acknowledged

Download Full-text

Socioeconomic Inequalities and Ethnicity Are Associated with a Positive COVID-19 Test among Cancer Patients in the UK Biobank Cohort

Cancers ◽

10.3390/cancers13071514 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1514

Author(s):

Shing Fung Lee ◽

Maja Nikšić ◽

Bernard Rachet ◽

Maria-Jose Sanchez ◽

Miguel Angel Luque-Fernandez

Keyword(s):

Cancer Patients ◽

Socioeconomic Inequalities ◽

Uk Biobank ◽

Incident Cancer ◽

Increased Risk ◽

Exposure Variable ◽

Independent Risk Factors ◽

The Uk ◽

Deprived Areas

We explored the role of socioeconomic inequalities in COVID-19 incidence among cancer patients during the first wave of the pandemic. We conducted a case-control study within the UK Biobank cohort linked to the COVID-19 tests results available from 16 March 2020 until 23 August 2020. The main exposure variable was socioeconomic status, assessed using the Townsend Deprivation Index. Among 18,917 participants with an incident malignancy in the UK Biobank cohort, 89 tested positive for COVID-19. The overall COVID-19 incidence was 4.7 cases per 1000 incident cancer patients (95%CI 3.8–5.8). Compared with the least deprived cancer patients, those living in the most deprived areas had an almost three times higher risk of testing positive (RR 2.6, 95%CI 1.1–5.8). Other independent risk factors were ethnic minority background, obesity, unemployment, smoking, and being diagnosed with a haematological cancer for less than five years. A consistent pattern of socioeconomic inequalities in COVID-19 among incident cancer patients in the UK highlights the need to prioritise the cancer patients living in the most deprived areas in vaccination planning. This socio-demographic profiling of vulnerable cancer patients at increased risk of infection can inform prevention strategies and policy improvements for the coming pandemic waves.

Download Full-text

Does early onset asthma increase childhood obesity risk? A pooled analysis of 16 European cohorts

European Respiratory Journal ◽

10.1183/13993003.00504-2018 ◽

2018 ◽

Vol 52 (3) ◽

pp. 1800504 ◽

Cited By ~ 15

Author(s):

Zuelma A. Contreras ◽

Zhanghua Chen ◽

Theano Roumeliotaki ◽

Isabella Annesi-Maesano ◽

Nour Baïz ◽

...

Keyword(s):

Allergic Rhinitis ◽

Childhood Asthma ◽

Early Onset ◽

Pooled Analysis ◽

Obesity Risk ◽

Obese Children ◽

The Past ◽

Increased Risk ◽

The Uk

The parallel epidemics of childhood asthma and obesity over the past few decades have spurred research into obesity as a risk factor for asthma. However, little is known regarding the role of asthma in obesity incidence. We examined whether early-onset asthma and related phenotypes are associated with the risk of developing obesity in childhood.This study includes 21 130 children born from 1990 to 2008 in Denmark, France, Germany, Greece, Italy, The Netherlands, Spain, Sweden and the UK. We followed non-obese children at 3–4 years of age for incident obesity up to 8 years of age. Physician-diagnosed asthma, wheezing and allergic rhinitis were assessed up to 3–4 years of age.Children with physician-diagnosed asthma had a higher risk for incident obesity than those without asthma (adjusted hazard ratio (aHR) 1.66, 95% CI 1.18–2.33). Children with active asthma (wheeze in the last 12 months and physician-diagnosed asthma) exhibited a higher risk for obesity (aHR 1.98, 95% CI 1.31–3.00) than those without wheeze and asthma. Persistent wheezing was associated with increased risk for incident obesity compared to never wheezers (aHR 1.51, 95% CI 1.08–2.09).Early-onset asthma and wheezing may contribute to an increased risk of developing obesity in later childhood.

Download Full-text

How important is the relative balance of fat and carbohydrate as sources of energy in relation to health?

Proceedings of The Nutrition Society ◽

10.1017/s0029665115004188 ◽

2015 ◽

Vol 75 (2) ◽

pp. 147-153 ◽

Cited By ~ 7

Author(s):

Thomas A. B. Sanders

Keyword(s):

Controlled Trial ◽

Dietary Guidelines ◽

Partial Replacement ◽

Current Evidence ◽

Added Sugar ◽

Increased Risk ◽

Total Fat ◽

Randomised Controlled ◽

Refined Carbohydrates ◽

The Impact

Both the intake of fat, especially saturated trans fatty acids, and refined carbohydrates, particularly sugar, have been linked to increased risk of obesity, diabetes and CVD. Dietary guidelines are generally similar throughout the world, restrict both intake of SFA and added sugar to no more than 10 and 35 % energy for total fat and recommend 50 % energy from carbohydrates being derived from unrefined cereals, tubers, fruit and vegetables. Current evidence favours partial replacement of SFA with PUFA with regard to risk of CVD. The translation of these macronutrient targets into food-based dietary guidelines is more complex because some high-fat foods play an important part in meeting nutrient requirements as well as influencing the risk of chronic disease. Some of the recent controversies surrounding the significance of sugar and the type of fat in the diet are discussed. Finally, data from a recently published randomised controlled trial are presented to show the impact of following current dietary guidelines on cardiovascular risk and nutrient intake compared with a traditional UK diet.

Download Full-text

Effect of riboflavin supplementation on blood pressure and possible effect modification by the MTHFR C677T polymorphism: a randomised trial in rural Gambia

F1000Research ◽

10.12688/f1000research.25113.1 ◽

2020 ◽

Vol 9 ◽

pp. 1034

Author(s):

Modou Jobe ◽

Mary Ward ◽

Bakary Sonko ◽

Abdul Khalie Muhammad ◽

Ebrima Danso ◽

...

Keyword(s):

Blood Pressure ◽

Large Scale ◽

Methylenetetrahydrofolate Reductase ◽

Controlled Trial ◽

Randomised Trial ◽

Mthfr C677t ◽

C677t Polymorphism ◽

Phenotypic Effect ◽

Riboflavin Deficiency ◽

Mthfr C677t Polymorphism

Introduction: Emerging evidence links a functional polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene (rs1801133) with hypertension in adults. This variant reduces the affinity of MTHFR for its cofactor flavin-adenine dinucleotide (FAD) which is derived from riboflavin. Previous work has demonstrated a blood pressure (BP)-lowering effect of riboflavin in Irish adults with the MTHFR 677TT variant. We hypothesize that the almost-universal severe riboflavin deficiency seen in rural Gambia mimics the BP phenotypic effect of the TT variant and exacerbate the effect of the CT variant. We will test this in a randomised, placebo-controlled trial, whether intervention with riboflavin can decrease BP in adults in rural Gambia. Methods: This is a phase 2 recall-by-genotype randomised single-blind placebo-controlled riboflavin supplementation trial. We will use the Keneba biobank to recruit approximately 102 individuals aged between 18-70, previously genotyped for the MTHFR C677T polymorphism and identified as carrying the T allele; these individuals will be age- and sex-matched to a similar number of homozygotes for the C allele. The participants will be randomised to a 16-week supplementation trial of 5 mg/day riboflavin or placebo, supplied every 14 days. The primary outcome, BP, will be measured at baseline and at weeks 8 and 16. Blood samples, collected at baseline and week 16, will be analysed for riboflavin, homocysteine, red cell folate, cobalamin (vitamin B12) and pyridoxine (vitamin B6). Discussion: The study will evaluate the role of riboflavin supplementation in BP control within a population with high levels of riboflavin deficiency and will test a possible gene-nutrient interaction with the MTHFR C677T polymorphism. If improvements in BP are observed in this study, and proven in subsequent large-scale interventions, riboflavin could offer a cost-effective, safe and accessible option for the prevention and control of hypertension in this population. Trial registration: ClinicalTrials.gov Identifier NCT03151096. Registered on 12 May 2017.

Download Full-text

Role of Bacterial Overgrowth in the Stomach as an Additional Risk Factor for Gastritis

Canadian Journal of Gastroenterology ◽

10.1155/2003/350347 ◽

2003 ◽

Vol 17 (suppl b) ◽

pp. 13B-17B ◽

Cited By ~ 15

Author(s):

Gregory Naylor ◽

Anthony Axon

Keyword(s):

Gastric Cancer ◽

Cell Mass ◽

Bacterial Overgrowth ◽

Nitroso Compounds ◽

Current Evidence ◽

Additional Risk Factor ◽

Proximal Small Bowel ◽

Increased Risk ◽

H Pylori

Gastric bacteria can either be ingested or ascend from the distal bowel; however, their survival is usually limited by gastric acidity and motility. A reduction in gastric acid can result in bacterial overgrowth in the stomach and proximal small bowel, and the number of organisms rises as the intragastric pH rises.The increased risk of noncardia gastric cancer seen in patients with hypochlorhydria may be explained by an excess of nitrites and N-nitroso compounds (NOCs). These compounds are found in the diet of populations with a high gastric cancer risk, but can also be produced by the organisms that exist in the hypochlorhydria stomach. It has long been hypothsized that nitrites and NOCs act as one of the triggers in the atrophy-metaplasia-dysplasia-carcinoma path. However, although indirect data have linked the premalignant changes of metaplasia and dysplasia to NOCs, direct measurement of gastric nitrites and NOCs has not confirmed such a link.The role ofHelicobacter pyloriin bacterial overgrowth is mainly as a cause of hypochlorhydria resulting from atrophic gastritis, leading to a reduction in the parietal cell mass.Acid-suppressing drugs can result in bacterial overgrowth and increased nitrites and NOCs, although there is no current evidence for an increased risk of gastric cancer in patients taking them. One explanation is that the stomach appears to be colonized by different organisms than those in patients with hypochlorhydria for other reasons. There is some evidence that bacterial overgrowth per se can cause gastric inflammation in mice; however, although in humans the degree of gastric inflammation is greater when overgrowth is more prominant this may simply reflect the greater degree of hypochlorhydria in patients with a more severe H pylori-induced inflammation.

Download Full-text