The regulation of aldosterone secretion is altered in essential hypertension: the phenotype of relative aldosterone excess is present in up to 15% of subjects. The gene encoding aldosterone synthase (CYP11B2) offers an obvious candidate to account for this and a polymorphism in its 5′ untranslated region (UTR; −344C/T) is associated with increased frequency of hypertension and higher aldosterone levels. However, this variation is more closely associated with an increase in the ratio of deoxycortisol to cortisol (S/F), a classic index of reduced efficiency of the 11β-hydroxylase enzyme encoded by the adjacent CYP11B1 gene which is expressed in zona fasciculata. We propose that this phenotypic association with CYP11B2 reflects variation in CYP11B1 and is accounted for by linkage disequilibrium (LD) between the genes. If so, the CYP11B2 polymorphisms should be linked to causal variants that alter 11β-hydroxylase activity.
Sequencing of the CYP11B locus revealed 83 polymorphisms; these formed 4 common haplotypes, accounting for 68% of chromosomes. Two novel CYP11B1 single nucleotide polymorphisms (SNPs) in the 5′ UTR (−1888 G/T, −1858 A/G) were in close LD with the −344C/T polymorphism in CYP11B2. There was a significant association between these polymorphisms and the ratio of urinary tetrahydrodeoxyxortisol (THS) to total cortisol (F) in a population of hypertensive patients (n=512), indicating impaired 11β-hydroxylase efficiency (see Table 1).
SNP effects on transcription efficiency were tested in vitro using a reporter gene system. Compared to wild type, constructs containing the −1888T and −1858G SNPs halved activity in the presence of ACTH (P<0.001) or forskolin (P<0.025), indicating reduced transcription. We conclude that CYP11B2 polymorphisms are in LD with novel SNPs in CYP11B1 which associate with impaired 11-hydroxylation as a result of reduced CYP11B1 transcription. We propose that this may result in small compensatory increases in ACTH drive which, long term, may lead to adrenal hyperplasia and hypertension associated with mineralocorticoid excess.