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.