Genomewide Association Between GLCCI1 and Response to Glucocorticoid Therapy in Asthma

Abstract

To determine the genetic basis for the individual variability response to inhaled glucocorticoid (ICS) therapy.The primary study population was the Childhood Asthma Management Program cohort of 1041 children with asthma who were 5 to 12 years old at enrollment. Additional subjects were selected from 3 other National Institutes of Health–sponsored clinical trials.The study analyzed a small number of statistically powerful variants selected on the basis of a family-based screening algorithm. Single-nucleotide polymorphisms predicted the changes in lung function response to ICS.Significant pharmacogenic association was found in the single-nucleotide polymorphism, rs37972, replicated in 4 independent populations totaling 935 persons (P = .0007), which maps to the glucocorticoid-induced transcript 1 gene (GLCCI1) and is in complete linkage disequilibrium (ie, perfectly correlated) with rs37973. Both rs37972 and rs37973 are associated with decrements in GLCCI1 expression. Overall, the mean 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%). The risk of poor response was significantly higher (odds ratio 2.36; 95% confidence interval 1.27–4.41) with genotype, accounting for 6.6% of overall ICS response variability.The functional GLCCI1 variant is associated with substantial decrements in response to ICS in patients with asthma.This study allows for better understanding of the mechanisms of ICS response. Although these data do not provide complete understanding of the mechanisms of ICS response, further insight is gained regarding the operative mechanisms.