(Hypertension. 2000;36:187.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
CA-Repeat Polymorphism in Intron 1 of HSD11B2
Effects on Gene Expression and Salt Sensitivity
From the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Tex (A.K.A., H.N., P.C.W.); the Division of Endocrinology, University of Ancona, Ancona, Italy (G.G., F.M.); the Division of Medical Sciences, University of Birmingham Queen Elizabeth Hospital, Birmingham, UK (G.L., M.R., C.McT., P.M.S.); Instituto di Ematologia e di Endocrinologia, Universita degli studi Sassari, Sassari, Italy (M.P.); the Division of Nephrology, Dialysis and Hypertension, University of Milan, S Raffaele Hospital, Milan, Italy (G.B., P.M.); and the Department of Clinical and Experimental Medicine, Federico II University of Naples Medical School, Naples, Italy (P.S.).
Correspondence to Perrin C. White, MD, Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75235-9063. E-mail pwhit2{at}mednet.swmed.edu
Abstract—Mutations in the HSD11B2 gene encoding the kidney (11-HSD2) isozyme of 11ß-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.
Key Words: polymorphism • gene expression • hypertension, genetic • dehydrogenases • dinucleotide repeat
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