Aldosterone synthase gene variation and adrenocortical response to sodium status, angiotensin II and ACTH in normal male subjects.
OBJECTIVE
Aldosterone synthase, a key enzyme in the terminal steps of aldosterone synthesis, is encoded by the CYP11B2 gene. A polymorphism in the 5' coding region of this gene (-344 C/T) is associated with hypertension, particularly with elevation of the aldosterone to renin ratio. A second polymorphism (a conversion in intron 2 to resemble that of the neighbouring 11beta-hydroxylase (CYP11B1) gene) is found in close linkage dysequilibrium with the variant at -344 C/T. The mechanism by which these variants predispose to cardiovascular disease and the precise intermediate phenotype associated with them remains speculative.


METHODS
We performed a focused physiological study in normal volunteers stratified by CYP11B2 genotype.


METHODS
Twenty-three subjects homozygous for the T allele and 21 homozygous for the C allele of the -344 C/T polymorphism of CYP11B2 were studied.


METHODS
Basal and angiotensin II stimulated plasma and 24-h urinary steroid excretion during low (60 mmol/day) and high (160 mmol/day) sodium intake and plasma steroids after ACTH stimulation were measured.


RESULTS
No influence of polymorphic variation on basal or stimulated plasma cortisol or aldosterone or other plasma steroid concentrations during either dietary phase was seen. However, excretion of tetrahydro-11-deoxycortisol (the urinary metabolite of 11-deoxycortisol), which is the precursor of cortisol) was increased in TT subjects during sodium restriction, consistent with impairment of zona fasciculata 11beta-hydroxylation.


CONCLUSIONS
We conclude that this polymorphism has no major influence on normal zona glomerulosa function but is associated with a change in 11beta-hydroxylation in the zona fasciculata. The mechanism remains uncertain, but alteration of 11-deoxycortisol levels without change in cortisol suggests altered efficiency of 11beta-hydroxylation. In the long term, this may lead to a minor but chronic increase in ACTH drive to the gland, which may have consequences for steroid synthesis and predispose to the risk of cardiovascular disease.
Kennon
Brian
B
MRC Blood Pressure Group, Division of Cardiovascular and Medical Sciences, University of Glasgow, Western Infirmary, Glasgow, UK.
Ingram
Mary C
MC
Friel
Elaine C
EC
Anderson
Niall H
NH
MacKenzie
Scott M
SM
Davies
Eleanor
E
Shakerdi
Loai
L
Wallace
A Michael
AM
Fraser
Robert
R
Connell
John M C
JM
D000302:Adrenal Cortex / Q000502:physiology*; D000324:Adrenocorticotropic Hormone / Q000008:administration & dosage*; D000328:Adult; D000450:Aldosterone / Q000097:blood; D000804:Angiotensin II / Q000008:administration & dosage*; D003345:Corticosterone / Q000097:blood; D003350:Cortodoxone / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000652:urine; D018592:Cross-Over Studies; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics*; D003900:Desoxycorticosterone / Q000097:blood; D004311:Double-Blind Method; D006720:Homozygote; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000652:urine; D007262:Infusions, Intravenous; D008297:Male; D011110:Polymorphism, Genetic / Q000235:genetics*; D012982:Sodium, Dietary / Q000008:administration & dosage*
D012982:Sodium, Dietary; D000804:Angiotensin II; D003900:Desoxycorticosterone; D000450:Aldosterone; C009412:tetrahydro-11-deoxycortisol; D000324:Adrenocorticotropic Hormone; D019405:Cytochrome P-450 CYP11B2; D003345:Corticosterone; D003350:Cortodoxone; D006854:Hydrocortisone