Genomewide Association betweenGLCCI1and Response to Glucocorticoid Therapy in Asthma

Abstract

BACKGROUND The response to treatment for asthma is characterized by wide interindividual variability, with a significant number of patients who have no response. We hypothesized that a genomewide association study would reveal novel pharmacogenetic determinants of the response to inhaled glucocorticoids. METHODS We analyzed a small number of statistically powerful variants selected on the basis of a family-based screening algorithm from among 534,290 single-nucleotide polymorphisms (SNPs) to determine changes in lung function in response to inhaled glucocorticoids. A significant, replicated association was found, and we characterized its functional effects. RESULTS We identified a significant pharmacogenetic association at SNP rs37972, replicated in four independent populations totaling 935 persons (P = 0.0007), which maps to the glucocorticoid-induced transcript 1 gene (GLCCI1) and is in complete linkage disequilibrium (i.e., perfectly correlated) with rs37973. Both rs37972 and rs37973 are associated with decrements in GLCCI1 expression. In isolated cell systems, the rs37973 variant is associated with significantly decreased luciferase reporter activity. Pooled data from treatment trials indicate reduced lung function in response to inhaled glucocorticoids in subjects with the variant allele (P = 0.0007 for pooled data). Overall, the mean (± SE) increase in forced expiratory volume in 1 second in the treated subjects who were homozygous for the mutant rs37973 allele was only about one third of that seen in similarly treated subjects who were homozygous for the wild-type allele (3.2 ± 1.6% vs. 9.4 ± 1.1%), and their risk of a poor response was significantly higher (odds ratio, 2.36; 95% confidence interval, 1.27 to 4.41), with genotype accounting for about 6.6% of overall inhaled glucocorticoid response variability. CONCLUSIONS A functional GLCCI1 variant is associated with substantial decrements in the response to inhaled glucocorticoids in patients with asthma. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00000575.)

Inhaled Corticosteroids in Lung Diseases

“…Factors associated with a diminished dose response to ICSs include genetic polymorphisms, COPD, smoking, severe asthma, obesity, and vitamin D insufficiency (8,(19)(20)(21)(22). Patients with asthma who are homozygous for the variant allele rs37973, which maps to the glucocorticoid-induced transcript 1 gene (GLCCI1), show about one third the lung function response of that of those homozygous for the wild-type allele (19).…”

“…Patients with asthma who are homozygous for the variant allele rs37973, which maps to the glucocorticoid-induced transcript 1 gene (GLCCI1), show about one third the lung function response of that of those homozygous for the wild-type allele (19). The variant occurs in about 16% of the population.…”

Treatment response heterogeneity in asthma: the role of genetic variation

“…Six GWAS studies reported genetic variants to be associated with treatment response [30][31][32][33][34][35], while a large recent GWAS did not find any significantly associated genetic variants [36]. The GWAS that did identify genetic variants to be associated with ICS response, all reported different genes to be most significantly associated with response to ICS.…”

“…The first GWAS on ICS response was published in 2011 by Tantisira and coworkers. They studied 118 child-parent trios included in the Childhood Asthma Management Program (CAMP), a multicenter RCT trial (discovery phase) and subsequently aimed to replicate identified variants in 935 asthmatic adults and children from four different replication populations [31]. Variation in the GLCCI1 gene, encoding the …”

Asthma phenotyping, therapy, and prevention: what can we learn from systems biology?

“…In this context, the reduced effectiveness of inhaled glucocorticoids is an important challenge. It seems to be partly associated with a polymorphism in the glucocorticoid-induced transcript 1 gene (44). Even more prominent may be the effect of differences in phenotypes; patient groups with high symptom levels but low eosinophilic inflammation seem to have only moderate benefit from inhaled glucocorticoids (3).…”