CA-Repeat Polymorphism in Intron 1 of HSD11B2

Abstract

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...

Apparent Mineralocorticoid Excess

“…Preliminary data suggest that impaired 11␤HSD2 activity is associated with an increased susceptibility of BP to salt load (38), an observation that is in line with the well-established concept that low-renin hypertension generally is considered a salt-sensitive form of high BP (39). It is interesting that this propensity for increased salt sensitivity in association with decreased activity of the 11␤HSD2 enzyme may be genetically determined by variants in the HSD11B2 promoter or by the presence of undetected mutations in the HSD11B2 gene itself (38,40), an issue that deserves further investigation. This hypothesis is supported by the clinical response in two of our patients (kindred 2 and 3), who showed a good BP response to salt restriction.…”

Salt-sensitive men show reduced heart rate variability, lower norepinephrine and enhanced cortisol during mental stress

“…Research suggests a reduced activity of 11b-hydroxysteroid dehydrogenase type 2 (11b HSD2) in essential hypertension and SS. [8][9][10][11][12] 11b HSD2 converts cortisol into its less active metabolite cortisone. In the case of absence of the enzyme, caused for example by mutations of the HSD11B2 gene, as in the rare syndrome of apparent mineralocorticoid excess, patients show increased tubular sodium retention, hypokalemia and severe hypertension.…”

Impaired 11-β Hydroxysteroid Dehydrogenase Type 2 Activity in Sweat Gland Ducts in Human Essential Hypertension

“…Although some authors 12 did not suggest that HSD2 variants contribute to hypertension, it has been shown that some polymorphisms may be associated with salt-sensitive hypertension. 7,[13][14][15] Other studies searched for functional alterations in renal HSD2 by comparison of urinary excretion of cortisol and its metabolites in normotensive and hypertensive subjects. In some cases, 6,16,17 the 5␤ tetrahydrocortisol (THF) plus 5␣ tetrahydrocortisol (␣THF)/tetrahydrocortisone (THE) or urinary free cortisol (UFF)/urinary free cortisone (UFE) ratios were found slightly elevated in hypertensive patients, while other reports 18,19 indicate no significant change between normotensive and hypertensive subjects.…”