Association of Glucocorticoid Receptor Polymorphism A3669G in Exon 9β 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, 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.