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 11 beta -hydrox ylase 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 ACT H. The gene (CYP11B1) coding for this enzyme is highly homologous with and lies a relatively short distance downstream from the gene coding for aldost erone synthase (CYP11B2) on chromosome 8. Two polymorphisms of CYP11B2 have been described. The first involves a change of -344C to T in a putative st eroidogenic factor-1 (SF-1) binding site and the other, the intron conversi on, an exchange of intron 2 for that of CYP11B1. These polymorphisms are in linkage dysequilibrium. Their effects on 11 beta -hydroxylation were studi ed. METHODS AND RESULTS Normal subjects (n = 135) were genotyped and those homo zygous for either or both the polymorphisms were given ACTH (250 mug, i.v.) . Plasma was sampled before and 30 minutes after administration. Basal conc entrations of DOC, corticosterone, 11-deoxycortisol and cortisol and respon ses of corticosterone and cortisol to ACTH were not affected by genotype. H owever, 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 g reater in subjects homozygous for SF-1 T and/or intron conversion than in t hose homozygous for SF-1 C and/or normal intron. CONCLUSIONS These results indicate different 11 beta -hydroxylase efficienc ies. Thus, variation in CYP11B2 appears to affect the product of CYP11B1. T he mechanism is unclear. The close proximity of the two genes may lead to c ompetition for transcription factors or specific differences in intron 2 ma y affect transcription. Alternatively, the polymorphisms may be acting as m arkers for adjacent functional genetic variations.