Altered corticosteroid biosynthesis in essential hypertension: A digenic phenomenon.
Aldosterone plays an important role in electrolyte and blood pressure homeostasis. Our studies have focused on the role of aldosterone in essential hypertension. We have shown that plasma aldosterone and ARR are heritable characteristics and that aldosterone concentrations in older subjects are inversely correlated with birthweight and positively correlated with blood pressure. Aldosterone levels are also associated with polymorphic variation in the CYP11B2 gene, which encodes aldosterone synthase, the enzyme responsible for aldosterone production. Interestingly, CYP11B2 polymorphisms are also associated with less efficient activity of 11beta-hydroxylase, encoded by the neighbouring, highly homologous CYP11B1 gene. We propose that a digenic effect leads to increased aldosterone production, with inefficient 11beta-hydroxylation causing a long-term increase in ACTH drive to the adrenal gland and enhanced expression of CYP11B2, thereby resulting in chronically raised aldosterone secretion in response to factors such as angiotensin II and potassium. In susceptible subjects this is likely, over many years, to result in hypertension with relative aldosterone excess.
MRC Blood Pressure Group, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, United Kingdom. ed18g@clinmed.gla.ac.uk
Eleanor
E
Davies
Scott M
SM
Mackenzie
E Marie
EM
Freel
Samantha
S
Alvarez-Madrazo
Robert
R
Fraser
John M C
JM
Connell
D000450:Aldosterone / Q000096:biosynthesis*; D001794:Blood Pressure / Q000502:physiology; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000378:metabolism; D011110:Polymorphism, Genetic; D013252:Steroid 11-beta-Hydroxylase / Q000378:metabolism
D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase