The SF1 site polymorphism of the aldosterone synthase gene (CYP11B2) influences urinary steroid production and pressor dose response to angiotensin II during dietary manipulation of the renin-angiotensin system
B Kennon, E Davies, MC Ingram, EC Friel, NH Anderson, R Fraser & JMC Connell
Background: A polymorphism within the CYP11B2 gene, characterised by a C/T substitution at position 344, the putative binding site for steroidogenic transcription factor1, has been shown to influence aldosterone excretion rate and blood pressure in essential hypertension.
Aims: Assess the effect of contrasting genotype for the SF1 site on urinary and plasma steroid production during dietary manipulation of the renin-angiotensin system and assess the pressor dose response to angiotensin II.
Methods: 44 males with contrasting genotype for the SF1 site (TT=23 and CC=21) performed 24hour urine collections for estimation of urinary steroid metabolites by GCMS, after 4 days low (60mmolday) and high (180mmolday) sodium diet. Plasma steroid and pressor responses to stepwise, incremental doses of angiotensin II were measured at the end of each dietary phase.
Results: During the ang II infusion plasma steroid production was similar in both groups. The pressor response in the TT group, assessed as the dose of ang II required to increase MAP by 20mmHg, was greater after low versus high salt (median 8.5 and 5.4nanograms kilogram minute, respectively, p=0.03). This was not apparent in the CC group (median 7.6 and 5.3, low and high salt respectively, p=0.31). The TT group had a higher urinary tetrahydrodeoxycortisol (THS) excretion rate compared to the CC group after low salt diet (mean 111.3 and 68.2micrograms deciliter respectively, p=0.01). A similar, but not significant, trend was apparent for THS after high salt diet (111.0 and 86.0micrograms deciliter, p=0.13).
Conclusions: The T344C polymorphism in the promoter region of the CYP11B2 gene influences urinary steroid excretion. The effect was seen in compounds derived from the zona fasciculata (ZF) implying a possible effect on activity of 11betahydroxylase. Alterations in 11beta hydroxylation have been reported in essential hypertension therefore, this polymorphism may provide a mechanistic explanation for this intermediate phenotype seen in essential hypertension.