Childhood Asthma Management Program Cohort Research Articles

Genomewide Association Between GLCCI1 and Response to Glucocorticoid Therapy in Asthma

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.

Age-related changes in the asthmatic phenotype in children

To review the changes in the asthma phenotype as children progress from childhood into young adulthood. Some children with asthma in the early school years improve symptomatically during adolescence and young adulthood, with less frequent remissions and increased relapse rates in those with severe symptoms. During remission of symptoms, lung function abnormalities, airway hyper-responsiveness, and airway inflammation often persist. New data from the Childhood Asthma Management Program cohort show progression of lung function abnormalities during adolescence. Most children with persistent asthma have persistent disease as adults, and lung function abnormalities continue to progress as these children age.