Interaction between one-carbon metabolism and epigenetic age in hypertension

Abstract

Hypertension (HTN) is the leading risk factor for cardiovascular disease. Emerging evidence supports interactions between epigenetic age acceleration (EAA), DNA methylation and blood pressure (BP) in HTN aetiology, however, studies remain conflicting. The MTHFR C677T polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR) is associated with HTN. Riboflavin, the MTHFR cofactor, lowers blood pressure in individuals homozygous for MTHFR 677TT genotype, however, the mechanism underpinning the role of this gene-nutrient interaction in HTN is unknown. The aim of this thesis was to investigate the association between EAA, DNA methylation and HTN and/or BP in the general population and in adults stratified by the MTHFR C677T polymorphism who were exposed to riboflavin supplementation. Systematic review and meta-analysis were conducted to determine the consensus on the association between epigenetic age, DNA methylation and HTN and/or BP in adults. Using linear modelling we conducted epigenome-wide association studies (EWAS) to examine associations between DNA methylation (Illumina Infinium MethylationEPIC) and clinically measured BP traits (SBP, DBP, PP, MAP and HTN) in Generation Scotland: Scottish Family Health Study (GS: SFHS, n=18,135). We also explored the association between EAA, and clinically measured BP and compared EAA between hypertensives, pre-hypertensives and normotensive counterparts stratified by age. In addition, epigenome-wide methylation was examined in participants stratified by MTHFR genotype, validating top hits in GS: SFHS and investigating nutrient-sensitive sites in a randomised control trial of riboflavin supplementation (GENOVIT, n=109,1.6mg/day for 16 weeks). Systematic qualitative analysis demonstrated global, gene-specific, and epigenome-wide methylation associated with HTN and/or BP. Furthermore, meta-analysis indicated that EAA measured by three epigenetic clock algorithms (Horvath, Hannum and PhenoAge) was positively associated with clinically measured HTN (β: 0.29, 95% Cl: 0.15-0.43; P<0.0001). In GS: SFHS, we identified 12 CpGs associated with all 5 clinically measured BP traits, 8 were novel associations with BP (P<3.6E-08), with the top significant CpG, cg06690548 annotated to SLC7A11. EAA in middle-aged individuals (40-60 years) was positively associated with BP and HTN(P<0.01) and SBP in younger adults (18-40 years) (P<0.05). Furthermore, EAA was higher in individuals with HTN than NT counterparts employing both the PhenoAge (P<0.001) and Hannum algorithms (P=0.026). In GENOVIT, significant methylation differences (P<0.05) between MTHFR 677 CC and TT genotype groups were identified at 11 CpGs which were validated in GS: SFHS (P<3.6E-08), 5 of these were novel. In response to riboflavin supplementation, a trend toward differential methylation was observed in individuals stratified by MTHFR 677 genotype. This thesis provides the first systematic evidence that EAA is associated with HTN and identifies novel CpG sites associated with clinically measured HTN and BP in a population-based cohort and in those stratified by genetic BP risk. Furthermore, we show EAA was strongly associated with BP and HTN in early and mid-life and may therefore provide an early indication of HTN to help identify those most at risk who would benefit from early lifestyle interventions. Perturbed one-carbon metabolism resulting from MTHFR C677T polymorphism results in altered epigenomic profiles of hypertension-associated genes, which may be sensitive to nutritional interventions with one-carbon metabolites. These novel findings support the use of epigenetic age and nutrigenomics as we implement and realise the potential of genomic medicine for earlier diagnosis and more effective management of HTN to impact public health.

Thesis is embargoed until 30th June 2026.

Date of Award	Jun 2024
Original language	English
Sponsors	Department for the Economy
Supervisor	Mary Ward (Supervisor) & Diane Lees-Murdock (Supervisor)