A common C677T polymorphism in the gene encoding the folate metabolising enzyme, methylenetetrahydrofolate reductase (MTHFR), is known from epidemiological and GWAS studies to be associated with an increased risk of hypertension and cardiovascular disease (CVD). In a series of randomised controlled trials (RCTs) previously conducted at this Centre, supplementation with riboflavin, the MTHFR cofactor, has been shown to lower blood pressure (BP) in hypertensive adults with the variant MTHFR 677TT genotype. No previous study has, however, considered the effect of this common genetic variant on BP in generally healthy adults. Moreover, trials conducted to date have focused
on brachial BP as the primary outcome measure; investigation of central BP and related haemodynamics, may help further our understanding of the role of this polymorphism in hypertension. In addition, the role of folic acid, either alone or in combination with riboflavin on BP has not yet been considered.
The overarching aim of this thesis, therefore, was to further investigate the role of onecarbon metabolism, B vitamin status and the MTHFR C677T polymorphism on BP and markers of vascular health, in apparently healthy adults. Observational analysis of 498 healthy individuals aged 18-65 years, stratified by MTHFR genotype demonstrated higher brachial and central BP indices in the TT, relative to CC or CT genotypes, with brachial systolic BP over 5 mmHg higher in the TT compared to the non-TT genotype (P<0.001), a phenotype evident from 18-65 years. There was evidence of a more pronounced phenotype observed in females, with an almost 10 mmHg difference in mean brachial systolic BP in females the TT compared to non-TT genotype: 134.9 (95% CI 132.1-137.6) vs 125.2 (95% CI 122.3-128.0) mmHg; P<0.001. RCT findings confirmed the BP effect of riboflavin, alone or in combination with folic acid, in lowering BP in adults with the MTHFR 677TT genotype, a trend which was greatest in those with a higher systolic BP at baseline (P=0.024). In a final study, metabolites within the one-carbon pathway were investigated in relation to this polymorphism. Significantly lower concentrations of the methyl donor, S-adenosylmethionine (SAM) were observed in TT relative to CC individuals (74.7 ± 21.0 vs 85.2 ± 22.6 nmol/L, P=0.013); correspondingly SAM concentrations increased by 17.3 ± 21.8 (P=0.021) in response to supplementation with riboflavin, suggesting elevated BP in susceptible adults may be explained, at least to some extent, by impaired methylation capacity.
In conclusion, this thesis presents novel data demonstrating that the MTHFR C677T polymorphism is associated with significantly higher brachial and central BP in apparently healthy adults. Furthermore, riboflavin alone, or in combination with folic acid, may be an important modulator of BP in adults with the variant genotype. Given the high prevalence of the MTHFR C677T polymorphism globally (i.e. 10%), and much higher in some populations, the findings of this thesis may have important implications for the prevention and treatment of hypertension in adults with this genetic risk factor.
- Blood pressure
- Methylenetetrahydrofolate reductase (MTHFR)
- Folic Acid
- Sadenosylmethionine (SAM)