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

Abstract

Background Corticosteroids exert their anti-inflammatory action by binding and activating the intracellular the glucocorticoid receptor (GR) hetero-complex. Objective Evaluate the genes HSPCB, HSPCA, STIP1, HSPA8, DNAJB1, PTGES3, FKBP5, and FKBP4 on corticosteroid response. Methods Caucasian asthmatics (382) randomized to once daily flunisolide or conventional inhaled corticosteroid therapy were genotyped. Outcome measures were baseline FEV1, % predicted FEV1, and % change in FEV1 after corticosteroid treatment. Multivariable analyses adjusted for age, gender, and height, were performed fitting the most appropriate genetic model based on quantitative mean derived from ANOVA models to determine if there was an independent effect of polymorphisms on change in FEV1 independent of baseline level. Results Positive recessive model correlations for STIP1 SNPs were observed for baseline FEV1 [rs4980524, p=0.009; rs6591838, p=0.0045; rs2236647, p=0.002; and rs2236648; p=0.013], baseline % predicted FEV1 [rs4980524, p=0.002; rs6591838, p=0.017; rs2236647, p=0.003; and rs2236648; p=0.008] ; % change in FEV1 at 4 weeks [rs4980524, p=0.044; rs6591838, p=0.016; rs2236647; p=0.01] and 8 weeks therapy [rs4980524, p=0.044; rs6591838, p=0.016; rs2236647; p=0.01]. Haplotypic associations were observed for baseline FEV1 and % change in FEV1 at 4 weeks therapy [p=0.05 and p=0.01, respectively]. Significant trends towards association were observed for baseline % predicted FEV1 and % change in FEV1 at 8 weeks therapy. Positive correlations between haplotypes and % change in FEV1 were also observed. Conclusions STIP1 genetic variations may play a role in regulating corticosteroid response in asthmatics with reduced lung function. Replication in a second asthma population is required to confirm these observations. Clinical Implications Identifying genes that regulate corticosteroid responses could allow a priori determination of individual responses to corticosteroid therapy, leading to more effective dosing and/or selection of drug therapies for treating asthma.

Glucocorticoid Genes and the Developmental Origins of Asthma Susceptibility and Treatment Response

“…Similar to our findings in bronchial brushing and biopsy specimens, inhaled budesonide treatment has previously been shown to increase FKBP5 expression in bronchial biopsy specimens of subjects with asthma (46). However, in a previous genetic association study, there was no association of genetic polymorphisms in FKBP5 with improved lung function in subjects with asthma treated with inhaled corticosteroids (47). Given its role in glucocorticoid signaling and its reproducible demonstration of induction of expression after inhaled corticosteroid treatment in subjects with asthma, FKBP5 warrants further investigation for its involvement in asthma pathogenesis and treatment response.…”

Glucocorticoid resistance in Crohn's disease and ulcerative colitis: an association study investigating GR and FKBP5 gene polymorphisms

“…Our data are consistent with those of a meta-analysis performed on patients with mood disorders, in which it was demonstrated that treatment response is associated with FKBP5 gene polymorphism rs4713916, but not with rs3800373 or rs1360780. 31 Similarly, Hawkins et al 32 demonstrated lack of association between rs3800373 and GC response in asthmatic subjects.…”

Genetic basis for personalized medicine in asthma

“…Hawkins and colleagues have recently reported that multiple SNPs in stress-induced phosphoprotein 1 (STIP1) were associated with variable FEV 1 responses to treatment with inhaled flunisolide in 382 asthma subjects [59]. This study interrogated SNPs spanning eight candidate genes and identified STIP1 SNPs rs4980524 (intron 1), rs6591838 (intron 1) and rs2236647 (intron 5) affecting percent change in FEV 1 in response to flunisolide at 4 and 8 weeks.…”

“…This study interrogated SNPs spanning eight candidate genes and identified STIP1 SNPs rs4980524 (intron 1), rs6591838 (intron 1) and rs2236647 (intron 5) affecting percent change in FEV 1 in response to flunisolide at 4 and 8 weeks. For example, rs4980524; AA = 5.10 ± 17.16, AC = 5.40 ± 19.00, CC = 11.03 ± 24.03; p = 0.044 at 4 weeks [59]. STIP1 is an adaptor protein that coordinates functions with HSP70 and may be involved in formation of the glucocorticosteroid receptor heterocomplex.…”