CA-repeat polymorphism in intron 1 of HSD11B2: Effects on gene expression and salt sensitivity

Anil K. Agarwal, Gilberta Giacchetti, Gareth Lavery, Heli Nikkila, Mario Palermo, Marie Ricketts, Claire McTernan, Giuseppe Bianchi, Paolo Manunta, Pasquale Strazzullo, Franco Mantero, Perrin C. White, Paul M. Stewart

Research output: Contribution to journalArticle

122 Citations (Scopus)

Abstract

Mutations in the HSD11B2 gene encoding the kidney (11-HSD2) isozyme of 11β-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 (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 increase in the ratio of urinary-free cortisol/urinary-free cortisone was lower in 33 salt-sensitive subjects (urinary-free cortisol/urinary-free cortisone 0.89±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 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.

Original languageEnglish (US)
Pages (from-to)187-194
Number of pages8
JournalHypertension
Volume36
Issue number2
StatePublished - 2000

Fingerprint

Introns
Salts
Gene Expression
Cortisone
Hypertension
Hydrocortisone
Collecting Kidney Tubules
Sodium
11-beta-Hydroxysteroid Dehydrogenases
Kidney
Diuresis
Furosemide
Intravenous Infusions
Isoenzymes
Reverse Transcription
Arterial Pressure
Alleles
Rabbits
Polymerase Chain Reaction
Mutation

Keywords

  • Dehydrogenases
  • Dinucleotide repeat
  • Gene expression
  • Hypertension, genetic
  • Polymorphism

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Agarwal, A. K., Giacchetti, G., Lavery, G., Nikkila, H., Palermo, M., Ricketts, M., ... Stewart, P. M. (2000). CA-repeat polymorphism in intron 1 of HSD11B2: Effects on gene expression and salt sensitivity. Hypertension, 36(2), 187-194.

CA-repeat polymorphism in intron 1 of HSD11B2 : Effects on gene expression and salt sensitivity. / Agarwal, Anil K.; Giacchetti, Gilberta; Lavery, Gareth; Nikkila, Heli; Palermo, Mario; Ricketts, Marie; McTernan, Claire; Bianchi, Giuseppe; Manunta, Paolo; Strazzullo, Pasquale; Mantero, Franco; White, Perrin C.; Stewart, Paul M.

In: Hypertension, Vol. 36, No. 2, 2000, p. 187-194.

Research output: Contribution to journalArticle

Agarwal, AK, Giacchetti, G, Lavery, G, Nikkila, H, Palermo, M, Ricketts, M, McTernan, C, Bianchi, G, Manunta, P, Strazzullo, P, Mantero, F, White, PC & Stewart, PM 2000, 'CA-repeat polymorphism in intron 1 of HSD11B2: Effects on gene expression and salt sensitivity', Hypertension, vol. 36, no. 2, pp. 187-194.
Agarwal AK, Giacchetti G, Lavery G, Nikkila H, Palermo M, Ricketts M et al. CA-repeat polymorphism in intron 1 of HSD11B2: Effects on gene expression and salt sensitivity. Hypertension. 2000;36(2):187-194.
Agarwal, Anil K. ; Giacchetti, Gilberta ; Lavery, Gareth ; Nikkila, Heli ; Palermo, Mario ; Ricketts, Marie ; McTernan, Claire ; Bianchi, Giuseppe ; Manunta, Paolo ; Strazzullo, Pasquale ; Mantero, Franco ; White, Perrin C. ; Stewart, Paul M. / CA-repeat polymorphism in intron 1 of HSD11B2 : Effects on gene expression and salt sensitivity. In: Hypertension. 2000 ; Vol. 36, No. 2. pp. 187-194.
@article{bba5e89c24bc4cf59257cbd8eb473c86,
title = "CA-repeat polymorphism in intron 1 of HSD11B2: Effects on gene expression and salt sensitivity",
abstract = "Mutations in the HSD11B2 gene encoding the kidney (11-HSD2) isozyme of 11β-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 (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 increase in the ratio of urinary-free cortisol/urinary-free cortisone was lower in 33 salt-sensitive subjects (urinary-free cortisol/urinary-free cortisone 0.89±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 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.",
keywords = "Dehydrogenases, Dinucleotide repeat, Gene expression, Hypertension, genetic, Polymorphism",
author = "Agarwal, {Anil K.} and Gilberta Giacchetti and Gareth Lavery and Heli Nikkila and Mario Palermo and Marie Ricketts and Claire McTernan and Giuseppe Bianchi and Paolo Manunta and Pasquale Strazzullo and Franco Mantero and White, {Perrin C.} and Stewart, {Paul M.}",
year = "2000",
language = "English (US)",
volume = "36",
pages = "187--194",
journal = "Hypertension",
issn = "0194-911X",
publisher = "Lippincott Williams and Wilkins",
number = "2",

}

TY - JOUR

T1 - CA-repeat polymorphism in intron 1 of HSD11B2

T2 - Effects on gene expression and salt sensitivity

AU - Agarwal, Anil K.

AU - Giacchetti, Gilberta

AU - Lavery, Gareth

AU - Nikkila, Heli

AU - Palermo, Mario

AU - Ricketts, Marie

AU - McTernan, Claire

AU - Bianchi, Giuseppe

AU - Manunta, Paolo

AU - Strazzullo, Pasquale

AU - Mantero, Franco

AU - White, Perrin C.

AU - Stewart, Paul M.

PY - 2000

Y1 - 2000

N2 - Mutations in the HSD11B2 gene encoding the kidney (11-HSD2) isozyme of 11β-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 (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 increase in the ratio of urinary-free cortisol/urinary-free cortisone was lower in 33 salt-sensitive subjects (urinary-free cortisol/urinary-free cortisone 0.89±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 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.

AB - Mutations in the HSD11B2 gene encoding the kidney (11-HSD2) isozyme of 11β-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 (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 increase in the ratio of urinary-free cortisol/urinary-free cortisone was lower in 33 salt-sensitive subjects (urinary-free cortisol/urinary-free cortisone 0.89±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 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.

KW - Dehydrogenases

KW - Dinucleotide repeat

KW - Gene expression

KW - Hypertension, genetic

KW - Polymorphism

UR - http://www.scopus.com/inward/record.url?scp=0033886829&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033886829&partnerID=8YFLogxK

M3 - Article

C2 - 10948076

AN - SCOPUS:0033886829

VL - 36

SP - 187

EP - 194

JO - Hypertension

JF - Hypertension

SN - 0194-911X

IS - 2

ER -