The syndrome of apparent mineralocorticoid excess (AME) is an inherited form of human hypertension thought to result from a deficiency of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD). This enzyme normally converts cortisol to inactive cortisone and is postulated to thus confer specificity for aldosterone upon the mineralocorticoid receptor. We have analysed the gene encoding the kidney isozyme of 11 beta HSD and found mutations on both alleles in nine of 11 AME patients (eight of nine kindreds). These mutations markedly affect enzymatic activity. They thus permit cortisol to occupy the renal mineralocorticoid receptor and thereby cause sodium retention and hypertension.

Genetic variations in or near the aldosterone synthase (CYP11B2) gene strongly affect left ventricular size and mass in young adults free of clinical heart disease. These polymorphisms may also influence the response of the left ventricle to increases in dietary salt.

Polymorphisms in or near the aldosterone synthase gene are associated with variations in aldosterone and 11-deoxycortisol production in males. This may modulate the activity of the renin-angiotensin system and thereby contribute to blood pressure regulation.

Abstract-Mutations in the HSD11B2 gene encoding the kidney (11-HSD2) isozyme of 11␤-hydroxysteroid dehydrogenase cause apparent mineralocorticoid excess, a form of familial hypertension. Because the hypertension associated with AME is of the salt-sensitive type, it seemed possible that decreases in 11-HSD2 activity might be associated with salt sensitivity. To examine this, Italians with mild hypertension underwent a protocol consisting of a rapid intravenous saline infusion and subsequent furosemide diuresis. To determine whether there were genetic associations between HSD11B2 and salt sensitivity, 198 Italians were genotyped for a CA repeat polymorphism (11 alleles) in the first intron. Increased differences in mean arterial pressure between the sodium loaded and depleted states were correlated with shorter CA repeat length (Rϭ0.214, Pϭ0.0025). The effect behaved as a recessive trait. This suggested that decreased HSD11B2 expression was associated with shorter CA repeat length. Furthermore, activity of renal 11-HSD2 as measured by an increase in the ratio of urinary-free cortisol/urinary-free cortisone was lower in 33 salt-sensitive subjects (urinary-free cortisol/urinary-free cortisone 0.89Ϯ0.04 [meanϮSE]) compared with 34 salt-resistant subjects (0.71Ϯ0.04, PϽ0.001). However, when minigenes containing either 14 or 23 CA repeats were transfected into rabbit or human kidney cortical collecting duct cells, the construct with 14 repeats was instead expressed at levels 50% higher than those of the construct with 23 repeats, as determined by reverse transcription-polymerase chain reaction. We conclude that polymorphisms in HSD11B2 and decreased 11-HSD2 activity are associated with sensitivity to sodium loading, but a functional explanation for these associations remains to be elucidated. Key Words: polymorphism Ⅲ gene expression Ⅲ hypertension, genetic Ⅲ dehydrogenases Ⅲ dinucleotide repeat T he syndrome of apparent mineralocorticoid excess (AME) is an autosomal recessive form of salt-sensitive hypertension caused by deficiency of the kidney isozyme of 11␤-hydroxysteroid dehydrogenase (11-HSD2). In this disorder, cortisol is not inactivated to cortisone. As a result, cortisol, which is usually a weak mineralocorticoid in vivo, occupies the mineralocorticoid receptor in target tissues such as the distal nephron and causes excessive sodium retention and potassium excretion. The disease is caused by mutations in the HSD11B2 gene encoding the enzyme, most of which severely affect its activity. 1 AME is a rare disorder, but mutations or polymorphisms with milder effects on activity might occur more frequently and could be a significant cause of hypertension in the general population. Although mutations that produce very mild effects on enzymatic activity have been identified in relatively mildly affected patients with AME, 2,3 such mutations seem to be rare in the general population. Other polymorphisms have been sought but have not been associated with variations in blood pressure. 4 Because the hypertension associate...