Hypertension, currently affecting 1 in 7 people in N. Ireland, is a major risk factor for cardiovascular disease, and in particular stroke. The 677TT genotype in MTHFR, carried by 10% of people in Northern Ireland, has been identified as a risk factor for hypertension. MTHFR, which is involved in one carbon metabolism, supplies methyl groups for regulation of gene expression by DNA methylation.
Riboflavin is a co-factor for MTHFR and this gene-nutrient interaction has been shown to play an important role in hypertension. We have previously shown that intervention with riboflavin lowers blood pressure specifically in people with the TT genotype, independent of concurrent antihypertensive therapy. The mechanism by which riboflavin regulates hypertension is not clear but it is apparent that other factors in addition to genotype are influencing this effect.
We have recently demonstrated, in NICHSA funded work, that DNA methylation differs in individuals stratified by their MTHFR genotype and is altered both globally and at key loci related to hypertension in TT individuals receiving riboflavin in randomised control trials. In initial epigenome-wide exploratory analysis comparing methylation in peripheral blood samples from 16 MTHFR TT individuals, 94.5% of the top 1000 genomic regions gained methylation in individuals following supplementation with riboflavin.
We now propose to extend this genome-wide DNA methylation analysis to gain further understanding of the blood pressure lowering mechanism of riboflavin. The findings of this study will provide important information regarding the mechanism linking this novel gene-nutrient interaction with hypertension.
Hypothesis and aims of project;
The overarching aim is to examine the effect of riboflavin (vitamin B2) on DNA methylation in hypertensive adults with the MTHFR 677TT genotype to gain an understanding of the role of riboflavin in blood pressure regulation and identify novel targets for hypertension treatment.
Hypothesis;
The MTHFR 677TT genotype is associated with DNA methylation patterns which render individuals susceptible to high BP. Riboflavin supplementation alters DNA methylation at key loci related to hypertension in TT individuals
Aims;
1.Assess genome-wide DNA methylation patterns of peripheral blood lymphocytes collected from randomised control trials of riboflavin supplementation specifically in individuals with the MTHFR 677TT genotype using Illumina EPIC array
2.Confirm DNA methylation changes at key loci identified using pyrosequencing
3.Investigate our findings in an independent dataset
4.Examine the role of DNA methylation in controlling gene expression at novel riboflavin-sensitive loci using DNMT knockout cell lines
Applicants should hold, or expect to obtain, a First or Upper Second Class Honours Degree in a subject relevant to the proposed area of study.
We may also consider applications from those who hold equivalent qualifications, for example, a Lower Second Class Honours Degree plus a Master’s Degree with Distinction.
In exceptional circumstances, the University may consider a portfolio of evidence from applicants who have appropriate professional experience which is equivalent to the learning outcomes of an Honours degree in lieu of academic qualifications.
If the University receives a large number of applicants for the project, the following desirable criteria may be applied to shortlist applicants for interview.
The University offers the following levels of support:
The following scholarship options are available to applicants worldwide:
These scholarships will cover full-time PhD tuition fees for three years (subject to satisfactory academic performance) and will provide a £900 per annum research training support grant (RTSG) to help support the PhD researcher.
Applicants who already hold a doctoral degree or who have been registered on a programme of research leading to the award of a doctoral degree on a full-time basis for more than one year (or part-time equivalent) are NOT eligible to apply for an award.
Please note: you will automatically be entered into the competition for the Full Award, unless you state otherwise in your application.
The scholarship will cover tuition fees at the Home rate and a maintenance allowance of £19,000 (tbc) per annum for three years (subject to satisfactory academic performance).
This scholarship also comes with £900 per annum for three years as a research training support grant (RTSG) allocation to help support the PhD researcher.
Due consideration should be given to financing your studies. Further information on cost of living
Submission deadline
Friday 7 February 2020
12:00AM
Interview Date
09 to 20 March 2020
Preferred student start date
Mid September 2020
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