CORTICOSTEROIDS IN ESSENTIAL-HYPERTENSION - MULTIPLE CANDIDATE LOCI AND PHENOTYPIC VARIATION

1. The role of genetically determined changes in adrenal steroid produ ction, metabolism and action in the pathogenesis of cardiovascular dis ease 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 pol ymorphism (Bcl1); subjects with contrasting genotypes show altered ski n vasoconstrictor responses to topically applied budesonide without an y significant change in leucocyte receptor binding characteristics. 3. In a case control study of patients with essential hypertension, we h ave shown evidence of reduced 11 beta-hydroxysteroid dehydrogenase act ivity, with an elevated ratio of cortisol to cortisone metabolites in urine. 4. The genes encoding 11 beta-hydroxylase and aldosterone synth ase are highly homologous. Studies in the Milan hypertensive rat show variation at this locus, which may account for the increased steroid s ynthesis noted in the hypertensive strain; in man, a chimaeric gene co mprising 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 conditi on. 5. Measurement of basal plasma steroid levels in subjects with ess ential hypertension show an increased ratio of 11-deoxycortisol/cortis ol, consistent with reduced activity of 11 beta-hydroxylase in the zon a fasciculata. 6. In summary, three loci involved in corticosteroid sy nthesis, metabolism and action can independently affect cardiovascular phenotypes; their roles in determining pathophysiological changes, in cluding hypertension, remain to be studied.