An influence of variation in the aldosterone synthase gene (CYP11B2) on corticosteroid responses to ACTH in normal human subjects.

OBJECTIVE Previous evidence suggests that the efficiency of 11β-hydroxylase is at least partly heritable and also that it may be mildly impaired in essential hypertension. In both cases, assessment of activity was based on the response of 11-deoxycorticosterone (DOC) and 11-deoxycortisol to ACTH. The gene (CYP11B1) coding for this enzyme is highly homologous with and lies a relatively short distance downstream from the gene coding for aldosterone synthase (CYP11B2) on chromosome 8. Two polymorphisms of CYP11B2 have been described. The first involves a change of −344C to T in a putative steroidogenic factor-1 (SF-1) binding site and the other, the intron conversion, an exchange of intron 2 for that of CYP11B1. These polymorphisms are in linkage dysequilibrium. Their effects on 11β-hydroxylation were studied. METHODS AND RESULTS Normal subjects (n = 135) were genotyped and those homozygous for either or both the polymorphisms were given ACTH (250 µg, i.v.). Plasma was sampled before and 30 minutes after administration. Basal concentrations of DOC, corticosterone, 11-deoxycortisol and cortisol and responses of corticosterone and cortisol to ACTH were not affected by genotype. However, the responses of DOC (P = 0·002 and P = 0·001, respectively) and 11-deoxycortisol (P = 0·025 and P = 0·002, respectively) were significantly greater in subjects homozygous for SF-1 T and/or intron conversion than in those homozygous for SF-1 C and/or normal intron. CONCLUSIONS These results indicate different 11β-hydroxylase efficiencies. Thus, variation in CYP11B2 appears to affect the product of CYP11B1. The mechanism is unclear. The close proximity of the two genes may lead to competition for transcription factors or specific differences in intron 2 may affect transcription. Alternatively, the polymorphisms may be acting as markers for adjacent functional genetic variations.