Association of glucocorticoid receptor polymorphism A3669G in exon 9beta with reduced central adiposity in women.
The glucocorticoid receptor (GR) may be a common link between human obesity/metabolic syndrome and Cushing's syndrome. The effects of glucocorticoids are mediated through the functional isoform, GRalpha. An alternative isoform, GRbeta, behaves as a dominant negative inhibitor of GRalpha and has been implicated as a contributing factor to glucocorticoid resistance. A naturally occurring ATTTA to GTTTA single nucleotide polymorphism (A3669G) located in the 3' end of exon 9beta results in increased stability of GRbeta mRNA and increased GRbeta protein expression. Enhanced GRbeta expression may result in greater inhibition of GRalpha transcriptional activity, resulting in glucocorticoid insensitivity. To test the hypothesis that the 3669G allele would result in a phenotype less likely to express features of glucocorticoid excess, we studied the prevalence of this polymorphism and its relationship with obesity and features of the metabolic syndrome in 322 Europid and 262 South-Asian subjects in northeast England. We report evidence that 3669G allele is associated with reduced central obesity in Europid women and a more favorable lipid profile in Europid men. These data suggest that the 3669G allele may attenuate the undesirable effects of glucocorticoids on fat distribution and lipid metabolism, although its penetrance may vary in different ethnic groups.
Syed
Akheel A
AA
School of Clinical Medical Sciences, University of Newcastle, Newcastle upon Tyne NE2 4HH, UK.
Irving
Julie A E
JA
Redfern
Christopher P F
CP
Hall
Andrew G
AG
Unwin
Nigel C
NC
White
Martin
M
Bhopal
Raj S
RS
Weaver
Jolanta U
JU
D050154:Adiposity / Q000235:genetics* / Q000502:physiology; D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D001794:Blood Pressure / Q000502:physiology; D015992:Body Mass Index; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D005091:Exons / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009765:Obesity / Q000097:blood / Q000235:genetics / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000502:physiology; D012737:Sex Factors; D049629:Waist-Hip Ratio; D044465:White People / Q000235:genetics
D008076:Cholesterol, HDL; D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha; C121943:glucocorticoid receptor beta; D002784:Cholesterol