Functional effects of polymorphisms in the human gene encoding 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1): a sequence variant at the translation start of 11β-HSD1 alters enzyme levels

Malavasi, E. L.V., Kelly, V., Nath, N., Gambineri, A., Dakin, R. S., Pagotto, U., Pasquali, R., Walker, B. R. and Chapman, K. E. (2010) Functional effects of polymorphisms in the human gene encoding 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1): a sequence variant at the translation start of 11β-HSD1 alters enzyme levels. Endocrinology, 151(1), pp. 195-202. (doi: 10.1210/en.2009-0663)

Abstract

Regeneration of active glucocorticoids within liver and adipose tissue by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) may be of pathophysiological importance in obesity and metabolic syndrome and is a therapeutic target in type 2 diabetes. Polymorphisms in HSD11B1, the gene encoding 11β-HSD1, have been associated with metabolic phenotype in humans, including type 2 diabetes and hypertension. Here, we have tested the functional consequences of two single nucleotide polymorphisms located in contexts that potentially affect tissue levels of 11β-HSD1. We report no effect of allelic variation at rs846910, a polymorphism within the 5′-flanking region of the gene on HSD11B1 promoter activity in vitro. However, compared with the common G allele, the A allele of rs13306421, a polymorphism located two nucleotides 5′ to the translation initiation site, gave higher 11β-HSD1 expression and activity in vitro and was translated at higher levels in in vitro translation reactions, possibly associated with a lower frequency of “leaky scanning.” These data suggest that this polymorphism may have direct functional consequences on levels of 11β-HSD1 enzyme activity in vivo. However, the rs13306421 A sequence variant originally reported in other ethnic groups may be of low prevalence because it was not detected in a population of 600 European Caucasian women.<p></p> A polymorphism in the 5’-flanking region in the gene encoding 11β-HSD1 shows no detectable effect on promoter activity, whereas a polymorphism at the translation start influences expression of the enzyme.<p></p>

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Dakin, Dr Rachel
• Authors: Malavasi, E. L.V., Kelly, V., Nath, N., Gambineri, A., Dakin, R. S., Pagotto, U., Pasquali, R., Walker, B. R., and Chapman, K. E.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Endocrinology
• Publisher: Endocrine Society
• ISSN: 0013-7227
• ISSN (Online): 1945-7170
• Copyright Holders: Copyright © 2010 The Endocrine Society
• First Published: First published in Endocrinology 151(1):195-202
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher