Date of Award

Summer 2017

Document type

Thesis

Degree Name

MD (Medical Doctor)

First Supervisor

Professor Alice Stanton

Keywords

Hypertension, Pharmacogenetics, Renin, Single Nucleotide Polymorphism

Abstract

A renin gene distal enhancer single nucleotide polymorphism, REN-5312C/T, has been reported to influence in vitro renin gene transcription in transfected human choriodecidual cells and in diseased kidney tissue in humans. The polymorphism has also been shown to have in vivo functional activity in humans, with carriage of the REN-5312T allele associated with elevated blood pressure.

A randomized, cross-over clinical trial in 98 patients was completed in order to determine whether or not REN-5312C/T would predict response to each of three blockers of the renin-angiotensin system (RAS). Blood pressure lowering responses were observed to be greater in REN-5312T allele carriers, and in REN-5312T allele carriers with high baseline BP and/or low baseline PRA levels.

In a tissue-based study in normal adrenal glands, we observed greater renin mRNA expression levels in REN-5312T allele carriers. This finding confirmed functional activity of REN-5312C/T in normal adrenal gland tissue.

The clinical trial findings illustrate the potential functionality of the REN-5312C/T polymorphism in determining optimal antihypertensive treatment for individual patients. It is plausible that greater tissue RAS activity of REN-5312T allele carriers is at least in part responsible for the greater antihypertensive effect of REN-5312 T-allele carriers with RAS blockade.

REN-5312C/T may yet become a genotype used in practice to identify patients who will gain maximal benefit from RAS blockade both in terms of blood pressure lowering and protection from end-organ damage.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

File Size

5.88 MB

Comments

A thesis submitted for the degree of Doctor of Medicine from the Royal College of Surgeons in Ireland in 2017.

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