Effect of variation in CYP11B1 and CYP11B2 on corticosteroid phenotype and hypothalamic-pituitary-adrenal axis activity in hypertensive and normotensive subjects.
BACKGROUND
Aldosterone is important in the development of hypertension. We have shown that a single nucleotide polymorphism (SNP) (-344T) in the 5' regulatory region (UTR) of the gene encoding aldosterone synthase (CYP11B2) associates with aldosterone excess and hypertension as well as altered adrenal 11-hydroxylation efficiency (deoxycortisol to cortisol). This conversion is carried out by the enzyme 11beta-hydroxylase, encoded by the adjacent gene, CYP11B1. We proposed that the effects of CYP11B2 are explained by linkage disequilibrium (LD) across the CYP11B locus. We have demonstrated high LD across this locus and identified two SNPs in the 5' UTR of CYP11B1 (-1859 G/T, -1889 A/G) that associate with reduced transcription in vitro and altered 11-hydroxylation efficiency in vivo. Accordingly, we hypothesized that the reduced adrenal 11-hydroxylation may lead to chronic resetting of the pituitary-adrenal axis, with chronically increased ACTH drive resulting in aldosterone excess.


METHODS
To test this, we examined hypothalamic-pituitary-adrenal (HPA) axis activity in hypertensive and normotensive individuals stratified according to genotype at CYP11B2 (-344T/C) and CYP11B1 (-1859 G/T, -1889 A/G). Fifty-six subjects homozygous for CYP11B2 SNP (27 TT, 12 CC), and 38 homozygous for CYP11B1 SNPs (18 TTGG, 20 GGAA) were recruited. Diurnal variation and the effects of dexamethasone suppression and ACTH stimulation on plasma aldosterone, cortisol and ACTH under controlled conditions were studied.


RESULTS
Subjects with SNPs associated with reduced 11-hydroxylation efficiency (-344T CYP11B2; TTGG CYP11B1) showed reduced inhibition of ACTH after dexamethasone (P = 0.05) and an altered cortisol-ACTH relationship (decreased cortisol-ACTH ratio, P < 0.02). The same individuals also demonstrated close correlations between plasma cortisol and aldosterone (-344T CYP11B2 r = 0.508, P < 0.004; TTGG CYP11B1 r = 0.563, P < 0.003) suggesting that there was common regulation (possibly ACTH) of these hormones in genetically susceptible subjects.


CONCLUSIONS
Variation in CYP11B2 and CYP11B1 associates with chronic up-regulation of the HPA axis. These novel data support the suggestion that chronic aldosterone excess, in genetically susceptible individuals, may be a consequence of increased ACTH drive to the adrenal and identify novel molecular mechanisms that may lead to the development of hypertension within the general population.
Freel
E M
EM
Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, G12 8TA, UK. emf12k@clinmed.gla.ac.uk
Ingram
M
M
Wallace
A M
AM
White
A
A
Fraser
R
R
Davies
E
E
Connell
J M C
JM
D000328:Adult; D016022:Case-Control Studies; D019405:Cytochrome P-450 CYP11B2 / Q000096:biosynthesis; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D006973:Hypertension / Q000201:enzymology* / Q000235:genetics*; D007030:Hypothalamo-Hypophyseal System / Q000201:enzymology*; D008297:Male; D010641:Phenotype; D010913:Pituitary-Adrenal System / Q000201:enzymology*; D013252:Steroid 11-beta-Hydroxylase / Q000096:biosynthesis; D015854:Up-Regulation
D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase