Endocrine Abstracts

Background: The enzymes 11beta-hydroxylase and aldosterone synthase are key control steps in regulation of cortisol and aldosterone synthesis. We have previously reported that polymorphic variation of the gene encoding aldosterone synthase (CYP11B2) is associated with altered efficiency of 11b-hydroxylation of the precursor of cortisol, deoxycortisol. In order to examine this relationship in greater detail, we have studied the pattern of steroid precursor metabolite excretion in a large collection of nuclear families
Methods: 573 individuals from 105 extended families ascertained through a hypertensive proband were studied. Excretion of tetrahydrodeoxycortisol (THS), and tetrahydrodeoxycorticosterone (THDOC)] in 24-hour urine collections was made by GCMS. The C-344T, intron conversion (IC), A3323G, A5160C, T5596C and T6547C SNPs of the aldosterone synthase (CYP11B2) gene were typed. Heritability of steroid phenotypes was determined by the MERLIN programme, and associations between SNP alleles and urinary steroids determined using the QTDT programme.
Results: The heritability of THS was 19.36%, and the heritability of THDOC did not differ significantly from zero. There was significant association between all the polymorphisms except T5596C with urinary THS level (p=0.0007), stronger association being observed with more 5' polymorphisms.
Discussion: Urinary levels of THS were found to be heritable, suggesting that production of the precursor steroid (deoxycortisol) is genetically regulated. This steroid is the substrate for 11beta-hydroxylase, and is the precursor of cortisol. Our data suggest that this step is a key control point in cortisol synthesis, and that variation in activity of the enzyme has physiological consequences. The relationship between polymorphisms in the gene encoding aldosterone synthase (CYP11B2) and this phenotype is of interest; the data are consistent with our earlier findings of an association between CYP11B2 and efficiency of 11beta-hydroxylation, and suggest that the causal QTL is likely to be in close linkage disequilibrium with these genetic variants.