Molecular and clinical studies of corticosteroid biosynthesis and regulation in hypertension

Freel, Ellen Marie (2006) Molecular and clinical studies of corticosteroid biosynthesis and regulation in hypertension. PhD thesis, University of Glasgow.

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Hypertension is a common disorder affecting a large heterogeneous patient population. Despite improved understanding of its pathophysiology and availability of effective treatment strategies, hypertension remains a major, potentially modifiable, risk factor for cardiovascular disease. Aldosterone, the principal human mineralocorticoid, is increasingly recognised as playing a significant role in cardiovascular morbidity and its role in hypertension has recently been re-evaluated with studies that suggest that increased aldosterone concentration (as defined by an elevated aldosterone to renin ratio - ARR) is a key phenotype in up to 15 per cent of hypertensive subjects. We have previously reported that polymorphisms of the gene (C to T conversion at position -344 and intron conversion (1C) in intron 2) encoding aldosterone synthase (CYP11B2) are associated with hypertension, particularly in individuals with a high ARR. In normotensives, the T and 1C alleles associate with raised basal and ACTH-stimulated levels of the 11-deoxysteroids, deoxycorticosterone and 11-deoxycortisol which are substrates for the enzyme 11beta-hydroxylase, encoded by the adjacent and homologous gene CYP11B1. This has led to speculation that the T and 1C alleles of CYP11B2 are in linkage disequilibrium (LD) with functional variants in CYP11B1 resulting in reduced efficiency of this enzyme. In order to maintain cortisol production, positive feedback to the pituitary leads to a subtle but more pronounced adrenocorticotrophic hormone (ACTH) drive to the adrenal cortex and enhanced synthetic capacity of the zona glomerulosa resulting in increased production of aldosterone and suppression of renin. Thus in such individuals, there should be recognisable, genotype dependent, changes in the pattern of adrenal steroid production as well as alteration in the cortisol/ACTH relationship. These data are also consistent with a contribution of ACTH to the production of aldosterone (in - 344T & CYP11B1 -1888T/ -1858G) leading to the eventual phenotype of hypertension with aldosterone excess. (Abstract shortened by ProQuest.).

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Endocrinology, Physiology
Colleges/Schools: College of Medical Veterinary and Life Sciences
Supervisor's Name: Connell, Prof. J.M.C. and Davies, Dr. Eleanor
Date of Award: 2006
Depositing User: Enlighten Team
Unique ID: glathesis:2006-71427
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 10 May 2019 10:49
Last Modified: 21 May 2021 09:43
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