CA-repeat polymorphism in intron 1 of HSD11B2 - Effects on gene expressionand salt sensitivity

Mutations in the HSD11B2 gene encoding the kidney (11-HSD2) isozyme of 11 b eta-hydroxysteroid dehydrogenase cause apparent mineralocorticoid excess, a form of familial hypertension, Because the hypertension associated with AM E is of the salt-sensitive type, it seemed possible that decreases in 11-HS D2 activity might be associated with salt sensitivity. To examine this, Ita lians with mild hypertension underwent a protocol consisting of a rapid int ravenous saline infusion and subsequent furosemide diuresis. To determine w hether 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 t he sodium loaded and depleted states were correlated with shorter CA repeat length (R=0.214, P=0.0025). 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 inc rease in the ratio of urinary-free cortisol/urinary-free cortisone was lowe r in 33 salt-sensitive subjects (urinary-free cortisol/urinary-free cortiso ne 0.89+/-0.04 [mean+/-SE]) compared with 34 salt-resistant subjects (0.71/-0.04, P<0.001). However, when minigenes containing either 14 or 23 CA rep eats were transfected into rabbit or human kidney cortical collecting duct cells, the construct with 14 repeats was instead expressed at levels 50% hi gher 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 s odium loading, but a functional explanation for these associations remains to be elucidated.