No association of glucocorticoid receptor polymorphisms with asthma and response to glucocorticoids.

Abstract

PURPOSE: Glucocorticoids are the most effective anti-inflammatory drugs in asthma therapy. They act via receptors localized in target cells that after activation by glucocorticoids may affect expression of inflammatory genes thus reducing inflammation in asthma. However, 10-20% of patients, particularly with severe, difficult-to-treat asthma may not respond well to glucocorticoids and remain symptomatic even after being treated with high doses of inhaled or systemic glucocorticoids. Therefore, we investigated if polymorphisms known to affect expression or function of the glucocorticoid receptor may be responsible for lower efficacy of steroid therapy and the need to use high doses of inhaled drug. MATERIAL AND METHODS: We analyzed 113 pediatric patients in age from 6 to 18 with diagnosed asthma, including 54 children with severe, difficult-to-treat asthma. The diagnosis was based on clinical manifestation, a lung function test, increased IgE level and positive skin prick tests. We also analyzed 123 healthy control subjects. The polymorphisms were genotyped with the use of PCR-RFLP method. Linkage disequilibrium analysis was performed using Haploview. RESULTS: We did not observe any significant differences between asthmatic and healthy children for any of the polymorphisms analyzed. Weak linkage between two of the four polymorphisms studied: rs41423247 and rs6195 (D'=1.0; LOD=2.91, r2=0.044) was found in linkage disequilibrium analysis. We did not find any association of GR polymorphisms with the dose of inhaled glucocorticoids needed to achieve asthma control in the group of patients. CONCLUSION: The results may suggest that studied polymorphisms of the GR gene are not associated with asthma susceptibility and do not influence response to inhaled glucocorticoids in our sample.