The glucocorticoid receptor heterocomplex gene STIP1 is associated with improved lung function in asthmatic subjects treated with inhaled corticosteroids

Background: Corticosteroids exert their anti-inflammatory action by binding and activating the intracellular glucocorticoid receptor heterocomplex. Objective: We sought to evaluate the genes HSPCB, HSPCA, STIP1, HSPA8, DNAJB1, PTGES3, FKBP5, and FKBP4 on corticosteroid response. Methods: White asthmatic subjects (n = 382) randomized to once-daily flunisolide or conventional inhaled corticosteroid therapy were genotyped. Outcome measures were baseline FEV₁, percent predicted FEV₁, and percent change in FEV₁ after corticosteroid treatment. Multivariable analyses adjusted for age, sex, and height were performed, fitting the most appropriate genetic model based on the quantitative mean derived from ANOVA models to determine whether there was an independent effect of polymorphisms on change in FEV₁ independent of baseline level. Results: Positive recessive model correlations for STIP1 single nucleotide polymorphisms were observed for baseline FEV₁ (rs4980524, P = .009; rs6591838, P = .0045; rs2236647, P = .002; and rs2236648; P = .013), baseline percent predicted FEV₁ (rs4980524, P = .002; rs6591838, P = .017; rs2236647, P = .003; and rs2236648, P = .008), and percent change in FEV₁ at 4 weeks (rs4980524, P = .044; rs6591838, P = .016; and rs2236647, P = .01) and 8 weeks (rs4980524, P = .044; rs6591838, P = .016; and rs2236647; P = .01) or therapy. Haplotypic associations were observed for baseline FEV₁ and percent change in FEV₁ at 4 weeks of therapy (P = .05 and P = .01, respectively). Significant trends toward association were observed for baseline percent predicted FEV₁ and percent change in FEV₁ at 8 weeks of therapy. Positive correlations between haplotypes and percent change in FEV₁ were also observed. Conclusions: STIP1 genetic variations might play a role in regulating corticosteroid response in asthmatic subjects with reduced lung function. Replication in a second asthmatic population is required to confirm these observations.