DNA methylation of hypertension-related genes and effect of riboflavin supplementation in adults stratified by genotype for the MTHFR C677T polymorphism

Sophia Amenyah, M Ward, Amy McMahon, Jennifer Deane, H McNulty, Catherine Hughes, J.J Strain, Geraldine Horigan, John Purvis, CP Walsh, Diane Lees Murdock

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Background: The interaction between genetic, epigenetic and environmental factors plays an important role in the aetiology of hypertension. GWAS and observational studies link the C677T polymorphism in methylenetetrahydrofolate reductase (MTHFR) with hypertension, while riboflavin, the MTHFR cofactor, has been shown to reduce blood pressure and global DNA methylation in homozygous (TT genotype) individuals. It is currently unclear whether riboflavin modulates DNA methylation of other hypertension-related genes.
Objectives: To compare DNA methylation of hypertension-related genes in adults stratified by MTHFR genotype and effect of riboflavin intervention in adults with the variant MTHFR 677TT genotype.
Method: Pyrosequencing was carried out for hypertension-related genes (ACE, AGTR1, GCK, GNA12, IGF2, MMP9 and NOS3) in blood samples from participants in previous trials (CC, n = 40; TT, n = 40). The effect of intervention with riboflavin (1.6 mg/d for16 weeks) or placebo on DNA methylation was investigated in adults with the variant MTHFR 677TT genotype (n = 80).
Results: Individuals with the MTHFR 677TT v CC genotype had significantly higher average DNA methylation at NOS3 (+1.66%, P = 0.044). In response to riboflavin supplementation in TT individuals, there was an increase in average DNA methylation at IGF2 (+1.09%, P = 0.019) and a decrease at ACE (−0.44%, P = 0.021) in females only. Specific CpG sites were hypomethylated in GNA12 and hypermethylated in AGTR1.
Conclusion: This study provides the first RCT evidence that riboflavin alters DNA methylation of hypertensionrelated genes in adults with the MTHFR 677TT genotype, providing some insight into mechanisms linking hypertension with the genotype-specific response of BP to riboflavin.
Original languageEnglish
Pages (from-to)233-239
Number of pages7
JournalInternational Journal of Cardiology
Early online date10 Sept 2020
Publication statusPublished (in print/issue) - 1 Jan 2021

Bibliographical note

Funding Information:
This work was funded by grants from Northern Ireland Chest Heart & Stroke Association (NICHS206_07; DLM & MW), DSM Nutritional Products (MW, HN, JJS and CH), ESRC/BBSRC (ES/N000323/1; CPW, HN & DLM). Sophia D. Amenyah was supported by a Vice Chancellor's Research Scholarship from Ulster University . The funding organizations had no role, in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

Publisher Copyright:
© 2020 Elsevier B.V.

Copyright 2020 Elsevier B.V., All rights reserved.


  • DNA methylation
  • Hypertension
  • NOS3
  • AGTR1
  • MTHFR C677T polymorphism
  • riboflavin
  • blood pressure
  • one-carbon metabolism
  • ACE


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