Functional Effects of Polymorphisms in the Human Gene Encoding 11 beta-Hydroxysteroid Dehydrogenase Type 1 (11 beta-HSD1): A Sequence Variant at the Translation Start of 11 beta-HSD1 Alters Enzyme Levels

Elise L. V. Malavasi, Val Kelly, Nikita Nath, Alessandra Gambineri, Rachel S. Dakin, Uberto Pagotto, Renato Pasquali, Brian R. Walker, Karen E. Chapman

Research output: Contribution to journalArticlepeer-review

Abstract

Regeneration of active glucocorticoids within liver and adipose tissue by the enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-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 11 beta-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 11 beta-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 11 beta-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 11 beta-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.

Original languageEnglish
Pages (from-to)195-202
Number of pages8
JournalEndocrinology
Volume151
Issue number1
DOIs
Publication statusPublished - Jan 2010

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