Endocrine Abstracts (2008) 15 P325

Heritability of plasma aldosterone levels and genetic variation association with the aldosterone synthase (CYP11B2) and 11beta-hydroxylase (CYP11B1) genes

Samantha Alvarez-Madrazo1, Sandosh Padmanabhan1, Michael Wallace2, Morvern Campbell1, Elaine Friel1, Bernard Keavney3, Eleanor Davies1 & John Connell1


1BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK; 2Department of Clinical Biochemistry, Glasgow Royal Infirmary, Glasgow, UK; 3Institute Human Genetics, University of Newcastle, Newcastle, UK.


Aldosterone plays a key role regulating electrolyte homeostasis and blood pressure. An elevated aldosterone to renin ratio is present in 15% of hypertensive patients but the causes of aldosterone excess are not fully understood. There is evidence of interaction between the polymorphisms in the aldosterone synthase gene (CYP11B2) and aldosterone levels in plasma and urine. However, the most consistent associations between variation at this locus and altered steroid synthesis have been found between the polymorphisms in the adjacent and homologous gene (CYP11B1) and a reduced efficiency in the enzyme it encodes, 11β-hydroxylase, which converts deoxycortisol to cortisol. To determine if plasma aldosterone levels are heritable and to test if variations in the CYP11B1/CYP11B2 locus can explain the variability of aldosterone levels, we used a large cohort of families ascertained from a hypertensive proband.

We genotyped 6 polymorphisms in CYP11B2 and 5 in CYP11B1 in 248 nuclear families. Plasma aldosterone was measured by radioimmunoassay in 805 individuals from 110 families and 63 individuals had aldosterone levels <70 pmol/l. The heritability was 14.6%.

A family based association analysis using FBAT, including and excluding individuals with aldo <70 pmol/l, yielded similar results. The CYP11B2 polymorphisms (intron 2 conversion P=0.027 and the synonymous SNP rs4538 in exon 6 P=0.018) showed strong association with aldosterone levels.

We have shown a significant element of heritability in plasma aldosterone variation. Our data suggest that causative polymorphisms are located in the CYP11B2 gene, although a separate influence of variation in the adjacent gene, CYP11B1, may also contribute. However, further studies defining fully the intermediate phenotype and genotype of these two genes in normal subjects and patients with hypertension are indicated to identify the way in which genetic and environmental factors interact to determine aldosterone and its exact role in hypertension.

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