Regulation of aldosterone and cortisol synthesis in hypertension and cardiovascular disease.

Lead Research Organisation: University of Glasgow
Department Name: College of Medical, Veterinary &Life Sci

Abstract

Hypertension is a very common health problem, and is perceived by the public as an important risk factor for cardiovascular disease. Better understanding of how genetic risk of hypertension interacts with environmental factors such as dietary sodium is important if members of the public are to be persuaded to alter lifestyle. We have already had experience of the interest that the lay public has in this area through the high level of participation in the Bright Study. The development of the UK Biobank programme over the next few years will offer an important DNA resource that will allow any key candidate genes that might have an important environmental interaction for a common disease to be studied in greater detail, and we propose to ensure that our links with the Biobank proposal through local and national collaborations are exploited in due course.

Technical Summary

The importance of aldosterone and cortisol in the underlying pathogenesis of cardiovascular disease and hypertension is increasingly recognized. Our studies focus on the enzymes which catalyse the terminal stages of cortisol (11beta-hydroxylase) and aldosterone (aldosterone synthase) biosynthesis and on the genes that encode them (CYP11B1 and CYP11B2).
During our current programme, we have demonstrated the heritable nature of aldosterone and cortisol synthesis. We have defined common polymorphic variants in CYP11B2 and shown them to be associated with increased aldosterone production, and with hypertension associated with a raised aldosterone to renin ratio. We have also shown that altered 11beta-hydroxylation is the most consistent phenotype associated with polymorphisms in CYP11B2 but have recently shown that this is likely to be a consequence of variation in the adjacent gene (CYP11B1) that encodes 11beta-hydroxylase. In addition, we have confirmed that these steroidogenic enzymes are produced and regulated not only in the adrenal cortex but also in the central nervous system (CNS).
Our future proposals build on our past studies and current programme. We plan to carry out a detailed evaluation of the corticosteroid phenotype in hypertension and relate precise genotype to phenotype, utilizing major population resources available to us. We propose functional genomic studies in humans in relation to variation in the late steroidogenic genes, and molecular studies to define the impact of variation at the CYP11B1 and CYP11B2 gene locus, relating functional changes to the 3D-stucture of the enzymes. Finally, we wish to evaluate the importance of corticosteroid synthesis biosynthesis in extra-adrenal sites.
In summary, using a wide range of clinical, cellular and molecular studies in humans and animals our aim is to define the way in which altered regulation of aldosterone and cortisol biosynthesis results in the common clinical phenotypes identified in cardiovascular disease.

Publications

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Alvarez-Madrazo S (2009) Familial and phenotypic associations of the aldosterone Renin ratio. in The Journal of clinical endocrinology and metabolism

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Alvarez-Madrazo S (2011) Role of genetic variation in regulation of aldosterone biosynthesis. in Endocrine development

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Arlt W (2010) Health status of adults with congenital adrenal hyperplasia: a cohort study of 203 patients. in The Journal of clinical endocrinology and metabolism

 
Description Membership of College/Faculty researcher development committee
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Policy Influence Type Influenced training of practitioners or researchers
Impact 2 members of group have held consecutive membership of this committee which directs and disseminates "Roberts" Funding to maximise value in training and career development of post-graduate scientists.
 
Description Membership of University Researcher Development committee
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact Membership of this committee, which develops University-wide policy for postgraduate career development. It also disseminates "Roberts" Funding to maximise value in training of post-graduate students and staff.
 
Description Science committee for Society for Endocrinology
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
Impact 2 members of group have held consecutive membership of this committee which directs scientific policy for the Society for Endocrinology. It also acts in an advisory capacity to influence science policy at UK/EU government level.
 
Description BHF Project Grant
Amount £88,500 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2010 
End 05/2013
 
Description Greek Government Scholarship
Amount £80,000 (GBP)
Organisation Government of Greece 
Sector Public
Country Greece
Start 10/2006 
End 09/2010
 
Description Hypertension Trust Studentship
Amount £68,000 (GBP)
Organisation The Hypertension Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2008 
End 03/2012
 
Description MRC Clinical Training Fellowship
Amount £187,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 07/2007 
End 07/2010
 
Description Medical Research Foundation
Amount £17,000 (GBP)
Organisation Medical Research Council (MRC) 
Department Medical Research Foundation
Sector Charity/Non Profit
Country United Kingdom
Start 04/2011 
End 05/2012
 
Description Mexican Government Scholarship
Amount £80,000 (GBP)
Organisation Government of Mexico 
Sector Public
Country Mexico
Start 10/2006 
End 04/2010
 
Description RCUK Fellowship
Amount £125,000 (GBP)
Organisation Research Councils UK (RCUK) 
Sector Public
Country United Kingdom
Start 04/2007 
End 04/2010
 
Description University of Glasgow Studentship
Amount £70,000 (GBP)
Organisation University of Glasgow 
Sector Academic/University
Country United Kingdom
Start 10/2009 
End 09/2012
 
Description University of Glasgow Studentship
Amount £70,000 (GBP)
Organisation Government of Scotland 
Department Scottish Funding Council
Sector Public
Country United Kingdom
Start 10/2007 
End 09/2010
 
Description University of Malaysia PhD student Scholarship
Amount £135,000 (GBP)
Organisation University of Malaya 
Sector Academic/University
Country Malaysia
Start 02/2012 
End 01/2015
 
Description Wellcome Trust VIP
Amount £20,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2008 
End 02/2009
 
Title DNA Genotyping 
Description Identification of new polymorphisms in steroidogenic genes and development of high throughput methodology to analyse these in large population studies. 
Type Of Material Technology assay or reagent 
Year Produced 2008 
Provided To Others? Yes  
Impact Research publications and development of collaborations with industrial sector. 
 
Title Mass spectrometry 
Description Use of Gas chromatography/mass spectroscopy to assay urinary steroid metabolite excretion - allows accurate quantification of adrenal steroid output for a range of steroids and offers the opportunity of conducting population surveys of steroid synthesis 
Type Of Material Technology assay or reagent 
Year Produced 2006 
Provided To Others? Yes  
Impact We have used this to identify key genetic determinants of adrenal cortex function and have correlated genotype, intermediate biochemical phenotype and clinical outcome. Development of collaborations with pharmaceutical industry. 
 
Description Hammer/Giordano 
Organisation Comprehensive Cancer Centre
Country United States 
Sector Hospitals 
PI Contribution Analysis of human adrenal gene expression
Collaborator Contribution Supply of rare human tissue for research study.
Impact Several conference research abstracts and a paper submitted to Molecular endocrinology this week
Start Year 2007
 
Title Corticosteroid analysis in cardiovascular disease 
Description LCMS assay of corticosteroids and genotyping assay to stratify patients with cardiovascular disease to identify response to targetted therapy. 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Initial development
Year Development Stage Completed 2008
Development Status Actively seeking support
Impact In development. 
 
Title GRA Assay 
Description PCR based technology to identify patients with Glucocorticoid suppressible hyperaldosteronism (GRA). We provide this service to Clinical Endocrinologists. 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2009
Development Status Under active development/distribution
Impact Positive Diagnosis of GRA. 
 
Description FOCUS West TopUp Programme, Glasgow 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Schools
Results and Impact The aim of this scheme is to help S5 and S6 pupils in schools where the percentage of pupils going to university is low, make informed choices regarding their higher education and promote science courses

Since this scheme starte, there has been and annual increase in the number of pupils from these schools applying factor and gaining admission to the HE sector.
Year(s) Of Engagement Activity 2007,2008,2009,2010
 
Description Royal Society MP/Scientist Exchange Scheme 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Primary Audience Policymakers/politicians
Results and Impact Local MP visited our Department on multiple occasions and group member attended parliament for 1 week to attend debates and to highlight the importance of scientific research.

Potential to be involved with the development and implementation of future scientific policy. In addition valuable networking links were established.
Year(s) Of Engagement Activity 2008,2009,2010
 
Description Society for Endocrinology (You and your hormones) 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Contributed to web-site information and reviewed content of web-site.

This web-site aims to give the general public and patients access to reliable online information on Endocrinology.
Year(s) Of Engagement Activity 2010
 
Description Soroptimists Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Presentation of work to lay public.

Research Donations
Year(s) Of Engagement Activity 2008,2009