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

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.

The Controversial Role of HCY and Vitamin B Deficiency in Cardiovascular Diseases

“…Even when folate availability is sufficient, deficiency of, another co-factor of MTHFR, can further reduce the residual MTHFR activity and thus limit the production of 5-MTHF. In this context, B2 deficiency has been found to increase the genetic risk of hypertension in individuals with the TT genotype [ 14 , 48 ]. However, remethylation of HCY is only of importance when methionine uptake via the food is low.…”

“…The common MTHFR C677T polymorphism is associated with a reduced enzyme activity, which can limit the availability of 5-MTHF in situations when folate supply is low [ 13 ]. Recent evidence suggests that riboflavin in the form flavin adenine dinucleotide (FAD) is a cofactor for MTHFR and may thus represent a key factor linking the MTHFR C677T polymorphism to CVD [ 14 ].…”

Gene-Gene Interaction Study Between Genetic Polymorphisms of Folate Metabolism and MTR SNPs on Prognostic Features Impact for Breast Cancer

“…Several studies have been reported on the association between the SNPs of the folate metabolizing genes Methylenetetrahydrofolate reductase (MTHFR) and Methionine synthase (MTR) genes with the changes that alter the primary structure of each protein, decrease enzymatic activity. This causes modification in DNA methylation profiles, abnormal gene expression and inactivation of tumor suppressor genes (4,13).…”

Methylenetetrahydrofolate reductase C677T gene polymorphism and the association with dyslipidemia in type 2 diabetic Palestinian patients

“…33 However, an observational data revealed that MTHFRTT genotype in 18-70 year old adults was associated with an increased risk of hypertension (systolic BP ≥ 140 and/or a diastolic BP ≥ 90 mmHg). 34 In addition, it was noted that the MTHFR C677T polymorphism significantly increased the risk of hypertension in rural Indonesian-Sudanese population. 35 On the other hand, although 65% of the studied subjects have diabetic complications, we could not find any association between the MTHFR C677T genotype distribution and the prevalence of CVD, DN and DR among the studied population (p > 0.05).…”

“…However, an observational data revealed that MTHFRTT genotype in 18–70 year old adults was associated with an increased risk of hypertension (systolic BP ≥ 140 and/or a diastolic BP ≥ 90 mmHg). 34 In addition, it was noted that the MTHFR C677T polymorphism significantly increased the risk of hypertension in rural Indonesian‐Sudanese population. 35 …”