Date of Award

2011

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Professor Alice Stanton

Second Supervisor

Dr Gianpiero Cavalleri

Third Supervisor

Professor Brian Harvey

Keywords

Cardiovascular Diseases - genetics

Abstract

This thesis consists of three different studies with the common aim of identifying novel genetic influences on cardiovascular risk in hypertensive individuals.

A candidate gene study was conducted to assess the association of genetic variation in the (pro)renin receptor ((P)RR), a recently-discovered member of the renin-angiotensin system, with blood pressure (BP) levels in two healthy Irish populations. We found a number of single nucleotide polymorphisms (SNPs) to be consistently associated with decreased BP (P

In two candidate pathway studies, we assessed genetic variation across genes in two biological pathways likely to play a role in BP regulation; ion channels (91 genes) and neurotransmitters (188 genes), for association with BP in two healthy Irish populations. We found that SNPs in a chloride channel gene, in a potassium channel gene and in a gene encoding a glutamate receptor precursor, were associated with increased BP with experiment-wide statistical significance.

Together, these targeted association studies have identified novel genes which have not been previously implicated in BP control, provide new insights into the pathophysiology of BP control, and may represent novel drug targets and/or pharmacogenetic markers.

Finally, a genome wide association study investigated the genetic determinants of two prostanoids, thromboxane (TxA2) and prostacyclin (PGI2), both of which play important roles in platelet and vascular homeostasis. In -800 Caucasian hypertensive subjects, 6 loci were statistically associated with levels of TxA2/ PGI2 at experiment-wide level. These associations were strongly influenced by use of aspirin, which inhibits production of these prostanoids. The genetic determinants of TxA2 and PGI2have not been examined before and the variants identified in this study may be novel predictors of atherothrombotic risk and help to inform the use of anti-platelet agents such as aspirin.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License.

File Size

7.83 MB

Comments

A thesis submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2011.

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