The glucocorticoid receptor (GR) is crucial for the effects of glucocorticoids (GCs). Several polymorphisms of the GR are associated with altered sensitivity to GCs. For the ER2223EK polymorphism, a relative GC resistance has been demonstrated. In vivo, this was suggested by a smaller response to a dexamethasone suppression test (DST), whereas in vitro experiments showed a diminished transactivational activity. The associated features of ER2223EK carriers consist of favorable metabolic and body compositional conditions. In elderly subjects this polymorphism was associated with longevity and decreased risk of dementia. Interestingly, recent studies also showed an increased risk of major depression. In contrast, the N363S polymorphism was reported to be associated with an enhanced sensitivity to GCs, as was demonstrated by a DST. This polymorphism has also been associated with increased body mass index (BMI) and LDL-cholesterol levels, as well as increased risk of cardiovascular disease. However, additional studies yielded conflicting results, showing no associations with being overweight. The BclI polymorphism is also associated with increased GC sensitivity. In addition, associations with increased abdominal fat mass, Crohn's disease and, remarkably, major depression have been reported. Another GR polymorphism, located in exon 9β, is associated with increased expression and stabilization of the dominant negative splice variant GR-β. Carriers of this polymorphism displayed a relative GC resistance in vitro as evidenced by diminished transrepressional activity, which is important for the immune system and inflammation. Associations have been found with increased inflammatory parameters, cardiovascular disease, and rheumatoid arthritis. In this article, studies concerning these clinically relevant GR variants are discussed.

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Keywords BclI polymorphism, ER2223EK polymorphism, Exon 9β, Glucocorticoid receptor (GR), N363S polymorphism
Persistent URL dx.doi.org/10.1111/j.1749-6632.2009.05013.x, hdl.handle.net/1765/27205
Citation
Manenschijn, L, van den Akker, E.L.T, Lamberts, S.W.J, & van Rossum, E.F.C. (2009). Clinical features associated with glucocorticoid receptor polymorphisms: An overview. New York Academy of Sciences. Annals, 1179, 179–198. doi:10.1111/j.1749-6632.2009.05013.x