title: 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.
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.
authors.affiliation: Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Elise L V
authors.initials: EL
authors.lastname: Malavasi
authors.forename: Val
authors.initials: V
authors.lastname: Kelly
authors.forename: Nikita
authors.initials: N
authors.lastname: Nath
authors.forename: Alessandra
authors.initials: A
authors.lastname: Gambineri
authors.forename: Rachel S
authors.initials: RS
authors.lastname: Dakin
authors.forename: Uberto
authors.initials: U
authors.lastname: Pagotto
authors.forename: Renato
authors.initials: R
authors.lastname: Pasquali
authors.forename: Brian R
authors.initials: BR
authors.lastname: Walker
authors.forename: Karen E
authors.initials: KE
authors.lastname: Chapman
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000502:physiology; D000293:Adolescent; D000328:Adult; D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D011085:Polycystic Ovary Syndrome / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000235:genetics; D014176:Protein Biosynthesis / Q000235:genetics* / Q000502:physiology; D055815:Young Adult
chemical_list: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human