Regulatory effect of common promoter polymorphisms on the expression of the 11beta-hydroxysteroid dehydrogenase type 1 gene.
OBJECTIVE
Glucocorticoids play an important role in the pathogenesis of obesity and insulin resistance. 11beta-hydroxysteroid dehydrogenase type 1 (HSD11B1), which converts inactive cortisone to active cortisol, has become an emerging therapeutic target for type 2 diabetes mellitus and obesity. In this study, we examined the association between HSD11B1 polymorphisms and type 2 diabetes and metabolic phenotypes in Koreans.


METHODS
We sequenced all exons including exon-intron boundaries and the promoter region of the HSD11B1 gene. Of 8 polymorphisms identified, we selected 4 common single-nucleotide polymorphisms (g.-19835G>A, g.-19609A>G, g.+27447G>C and g.+27810C>T) based on location, linkage disequilibrium and frequency and which were genotyped in 757 subjects with type 2 diabetes and 644 nondiabetic subjects.


RESULTS
There was no association between the 4 common polymorphisms of HSD11B1 and type 2 diabetes. g.-19835G>A and g.-19609A>G showed modest associations with fasting plasma glucose and body mass index but the significance of these associations was lost after adjustment for multiple comparison. With regard to promoter polymorphisms in the HSD11B1 gene, a haplotype construct carrying both g.-19835A and g.-19609G showed significantly decreased promoter activity compared to other common haplotype constructs.


CONCLUSIONS
The variations in HSD11B1 were not associated with susceptibility to type 2 diabetes or metabolic phenotypes in Koreans. However, the common promoter variants of the gene might exert a polymorphic regulatory effect on HSD11B1 expression.
Ku
Yun Hyi
YH
Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
Koo
Bo Kyung
BK
Kwak
Soo Heon
SH
Cho
Young Min
YM
Shin
Hyoung Doo
HD
Lee
Hong Kyu
HK
Kim
Yeonjung
Y
Choi
Jung-Won
JW
Oh
Bermseok
B
Park
Kyong Soo
KS
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics; D000368:Aged; D044466:Asian People / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D006801:Humans; D007723:Korea; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012045:Regulatory Sequences, Nucleic Acid
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human