Characterization of the BclI polymorphism in the glucocorticoid receptor gene.

Abstract

Glucocorticoids (GCs) have a major antiproliferative effect, which has led to the use of their synthetic homologs for immunosuppression, treatment of inflammation, and induction of cytotoxicity (1)(2). GCs exert their effect by binding to an intracellular GC receptor (GR), forming a complex that translocates to the nucleus, where GCs then regulate the expression of target genes interacting with promoter GC-responsive elements (1). The different GR forms, resulting from GR gene variability, can affect the regulation of many biological functions, such as hypothalamic-pituitary-adrenal axis regulation and GC responsiveness, thereby underlying susceptibility to many diseases. Indeed, GR mutations have been associated with altered cardiovascular function, metabolic disturbances, and hematologic malignancies (3)(4)(5). Likewise, functional GR variability might affect the therapeutic response to corticosteroid drugs (5). Identification of different GR gene variants may thus be helpful in assessing the role of the GR gene in disease susceptibility or in adjudging predisposition to corticosteroid-associated adverse drug reactions. Several polymorphisms of the GR gene, which might have an impact on GC sensitivity, have been reported (6)(7)(8). Among these, the Bcl I polymorphism was identified by Southern blotting using human GR cDNA-specific probes (9) that identified two alleles with fragment lengths of 4.5 and 2.3 kb. Several clinical investigations have subsequently suggested that this GR polymorphism is linked to altered GR function (6)(10)(11)(12)(13)(14)(15). An association between the Bcl I polymorphism and changes in tissue-specific corticosteroid sensitivity, as well as with poor feedback regulation of the hypothalamic-pituitary-adrenal axis, has been reported (6)(10). This was further documented by association of the Bcl I polymorphism with abdominal obesity (11)(12), insulin resistance (6)(13), and development of an atherogenic profile (6)(14). Similarly, …