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.
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.
Malavasi
Elise L V
EL
Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
Kelly
Val
V
Nath
Nikita
N
Gambineri
Alessandra
A
Dakin
Rachel S
RS
Pagotto
Uberto
U
Pasquali
Renato
R
Walker
Brian R
BR
Chapman
Karen E
KE
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
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human