Glucocorticoids And Treatment Response

Glucocorticoids remain the mainstay anti-inflammatory agents used in the management of asthma and many other inflammatory lung diseases, including most forms of interstitial lung disease, and moderate and severe COPD. In all these conditions it is clear that response is variable, with some patients responding well to inhaled or oral corticosteroids, and others having little or no response. A number of groups have therefore attempted to identify genetic markers associated with treatment response, initially concentrating on the glucocorticoid receptor itself and more recently expanding to study other potential genes that may modify the responses. In general, these studies are relatively difficult to perform mainly because it is difficult and time consuming to get a good measure of treatment response to glucocorticoids. For example, the degree of response in a condition, such as idiopathic pulmonary fibrosis, will often take weeks or months to become apparent and will also depend on the exact subtype of the disease present defined by high-resolution CT imaging or biopsy. Not all patients will have treatment with the same regimen of steroids, and follow-up may also differ between patient groups, all of which makes assessment of true treatment response more difficult. Again, the majority of studies that have been undertaken in asthma have, in particular, recognized a subgroup of "steroid-resistant" asthmatics, although again adequate phenotypic definition of these patients is difficult and time consuming.

Glucocorticoids bind to a cytoplasmic receptor, the glucocorticoid receptor, which moves to the nucleus and activates steroid-responsive genes containing the glucocorticoid response element (GRE). The receptor exists as at least two splice variants, which differ in the ninth exon. Several polymorphisms have been described in the glucocorticoid receptor (GR) gene, which produce functional consequences; for example, a Val641Asp polymorphism influences the binding affinity for dexamethasone (49), a Val729Ile polymorphism confers a fourfold decrease in dexamethasone activity (50), a Asn363Ser polymorphism is associated with higher sensitivity to dexamethasone (51), and 2314insA and S651F variants have suppressed GR mRNA and protein levels in a recombinant system (52). However, several of these polymorphisms are rare and their functional significance at a clinical level is unclear. Subsequently, haplotype identification across the GR gene identified a susceptibility haplotype associated with a lower response to dexa-methasone using a suppression test in 216 U.K. Caucasians (53).

Recently, sequence variation in the corticotrophin-releasing hormone receptor 1 (CRHR1) gene was found to be associated with enhanced response to therapy in three asthmatic cohorts (n = 1117, endpoint percent change in FEVj following eight weeks inhaled corticosteroid treatment) (54). The CRHR1 is thought to be involved in the regulation of endogenous levels of corticosteroid and, therefore, may be predicted to influence responses to exogenously administered corticosteroid. This study is the only study to show a pharmacogenetic effect for steroid efficacy in an asthmatic cohort and involved the analysis of 131 SNPs in 14 genes prior to the identification of the positive association described previously (54).

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