Corticosteroids in essential hypertension: multiple candidate loci and phenotypic variation.
1. The role of genetically determined changes in adrenal steroid production, metabolism and action in the pathogenesis of cardiovascular disease in man is considered by studying three loci that are important in corticosteroid function. 2. Variation at the glucocorticoid receptor locus can be identified as a biallelic restriction fragment length polymorphism (Bcl1); subjects with contrasting genotypes show altered skin vasoconstrictor responses to topically applied budesonide without any significant change in leucocyte receptor binding characteristics. 3. In a case control study of patients with essential hypertension, we have shown evidence of reduced 11 beta-hydroxysteroid dehydrogenase activity, with an elevated ratio of cortisol to cortisone metabolites in urine. 4. The genes encoding 11 beta-hydroxylase and aldosterone synthase are highly homologous. Studies in the Milan hypertensive rat show variation at this locus, which may account for the increased steroid synthesis noted in the hypertensive strain; in man, a chimaeric gene comprising 5' regulatory regions from 11 beta-hydroxylase and 3' coding sequence from aldosterone synthase accounts for the autosomal dominant condition Dexamethasone Suppressible Hyperaldosteronism. Variation in the precise location of the crossover site between the two genes does not account for the observed phenotypic heterogeneity in this condition. 5. Measurement of basal plasma steroid levels in subjects with essential hypertension show an increased ratio of 11-deoxycortisol/cortisol, consistent with reduced activity of 11 beta-hydroxylase in the zona fasciculata. 6. In summary, three loci involved in corticosteroid synthesis, metabolism and action can independently affect cardiovascular phenotypes; their roles in determining pathophysiological changes, including hypertension, remain to be studied.
Connell
J M
JM
Department of Medicine and Therapeutics, University of Glasgow, United Kingdom.
Kenyon
C J
CJ
Ingram
M
M
Holloway
C
C
Jamieson
A
A
Panarelli
M
M
Inglis
G
G
Fraser
R
R
D000305:Adrenal Cortex Hormones / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D016022:Case-Control Studies; D006801:Humans; D006973:Hypertension / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000502:physiology*
D000305:Adrenal Cortex Hormones; D011965:Receptors, Glucocorticoid