Endocrine Abstracts (2005) 9 P134

Haplotype analysis of the aldosterone synthase (CYP11B2) and 11beta-hydroxylase gene (CYP11B1) locus

M Barr, DM Wilkinson, EM Freel, SM MacKenzie, N Brain, R Fraser, E Davies & JMC Connell


Division of Cardiovascular And Medical Sciences, Western Infirmary, Glasgow, UK.


We have shown that linked polymorphisms in the aldosterone synthase gene (CYP11B2) are associated with hypertension and altered aldosterone production. However, the most consistent intermediate phenotype associated with this genetic variation is increased plasma 11-deoxycortisol (S) and urinary excretion of its metabolite, tetrahydrodeoxycortisol (THS); this is paradoxical as S is a substrate for the enzyme 11beta-hydroxylase, encoded by the neighbouring gene, CYP11B1. However, we have recently shown in the Oxford Hypertension Study of nuclear families that urinary THS excretion associates most strongly with an exon 1 polymorphism in CYP11B1, suggesting that the true QTL for the phenotype is within this gene. Accordingly, we have conducted a more detailed evaluation of the pattern of variation across this locus.

We carried out detailed sequencing and analysed the pattern of variation across the whole CYP11B1/B2 locus in homozygous subjects, using PHASE to reconstruct haplotypes from genotypes at 83 polymorphic loci spanning 45kb. This identified 4 haplotypes with frequencies >5% indicating considerable conservation of linkage disequilibrium (LD) across the region. These 4 haplotypes describe 68% of chromosomes in the sample. Calculated pairwise D' values between all loci were 0.70 to 1.00 indicating strong LD.

Many identified polymorphisms are intronic or conservative. However, nine are in the 5'UTRs of CYP11B1 and CYP11B2 and may affect gene expression through altered binding of transcription factors. The CYP11B1 5'UTR polymorphisms may be involved in the altered 11beta-hydroxylase efficiency we have consistently found to be associated with CYP11B2 polymorphisms. Reporter gene studies are currently determining their function. We suggest that a genetically determined minor decrease in 11beta-hydroxylase activity may result in chronic activation of the HPA axis and a lifetime increased exposure of the adrenal cortex to ACTH. Over prolonged periods, this may be relevant to the pathogenesis of essential hypertension and to the development of relative aldosterone excess.

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