Clinical Features Associated with Glucocorticoid Receptor Polymorphisms

Abstract

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 ER22/23EK 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 ER22/23EK 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 9beta, is associated with increased expression and stabilization of the dominant negative splice variant GR-beta. 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.

Association of glucocorticoid receptor polymorphism A3669G with decreased risk of developing diabetes in patients with Cushing's syndrome

“…Several previous studies have shown that polymorphisms of the GR are associated with altered sensitivity to GCs: in particular, the BclI polymorphisms of the GR gene have been associated with an enhanced sensitivity to GCs and consequently to a worse metabolic and bone profile in the general population (10,(12)(13)(14)(15). Patients with subclinical hypercortisolism were recently investigated by Morelli et al (36) to evaluate the role of the GR polymorphisms in metabolic or bone alterations in patients with adrenal incidentalomas (AI) without features of overt hypercortisolism.…”

“…Several investigations have shown that polymorphisms of the GR (NR3C1) may be associated with altered sensitivity to GCs leading to negative or positive effect on metabolic profile (10).…”

Adrenal insufficiency during treatment for childhood acute lymphoblastic leukemia is associated with glucocorticoid receptor polymorphisms ER22/23EK and BclI

“…The ER22/23EK polymorphism (rs6189 and rs6190, G>A, located on exon 2) and the GRb polymorphism (rs6198, A>G, located on exon 9b) have both been associated with a relative glucocorticoid resistance. 7,8 In contrast, the N363S polymorphism (rs56149945, previously rs6195, A>G, located in codon 363 of exon 2) and the BclI polymorphism (rs41423247, C>G, located 646 nucleotides downstream from exon 2) have been reported to be associated with an enhanced sensitivity to glucocorticoids. 7,9 We performed a pilot study to explore the relation between the duration of adrenal insufficiency after a 4-week induction course with high-dose prednisone therapy (60 mg/m 2 /day in three doses) with tapering over nine days and the incidence of GR polymorphisms with previously reported altered sensitivity for glucocorticoids in children treated according to the Dutch Childhood Oncology Group ALL 10 or the consecutive ALL 11 protocol.…”

“…The duration of adrenal insufficiency in carriers of ER22/23EK was shorter than in the non-carriers (median 7 In conclusion, the duration of adrenal insufficiency after discontinuation of a 4-week high-dose prednisone induction course is affected by GR genotype, which to the best of our knowledge has never been previously reported. The duration of adrenal insufficiency in carriers of the ER22/23EK polymorphism 7,8 was shorter than in non-carriers, indicating a lower susceptibility for developing adrenal insufficiency after high-dose glucocorticoid therapy. Adrenal insufficiency in patients homozygous for BclI 7,9 lasted longer in comparison to patients who were not homozygous for BclI.…”

“…The duration of adrenal insufficiency in carriers of the ER22/23EK polymorphism 7,8 was shorter than in non-carriers, indicating a lower susceptibility for developing adrenal insufficiency after high-dose glucocorticoid therapy. Adrenal insufficiency in patients homozygous for BclI 7,9 lasted longer in comparison to patients who were not homozygous for BclI. This indicates that patients homozygous for BclI have an increased susceptibility for prolonged adrenal insufficiency.…”