Akheel A. Syed1,2, Julie Irving1, Christopher P.F. Redfern1,2, Andrew G. Hall1, Nigel Unwin2,3, Martin White3, Raj Bhopal4, Jolanta U. Weaver2
1Northern Institute for Cancer Research, University of Newcastle, Newcastle Upon Tyne, United Kingdom
2School of Clinical Medical Sciences, University of Newcastle, Newcastle upon Tyne, United Kingdom
3School of Population and Health Sciences, University of Newcastle, Newcastle upon Tyne, United Kingdom
4Public Health Sciences Section, University of Edinburgh Medical School, Edinburgh, United Kingdom.
Tóm tắt
AbstractThe 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, GRα. An alternative isoform, GRβ, behaves as a dominant negative inhibitor of GRα 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 9β results in increased stability of GRβ mRNA and increased GRβ protein expression. Enhanced GRβ expression may result in greater inhibition of GRα 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.
