Late-breaking abstract: Genome-wide association of GLCCI1 with asthma steroid treatment response

Background: Asthma treatment response is characterized by wide inter-individual variability and a significant number of non-responders. Aims: We hypothesized that a genome-wide association study would yield novel determinants of inhaled glucocorticosteroid (ICS) response in asthma. Methods: We analyzed change in FEV 1 following ICS usage in a small number of statistically powerful variants selected via a family-based screening algorithm on 534,290 single nucleotide polymorphisms genotyped in the Childhood Asthma Management Program. Finding a significant, replicated association, we characterized its functional effects. Results: We identified a significant pharmacogenetic association at rs37972, which was replicated in four independent populations totaling 935 individuals (p=0.0007). This variant maps to the glucocorticoid induced transcript 1 (GLCCI1) gene and is in complete linkage disequilibrium (i.e., perfectly correlated) with rs37973; both are associated with decrements in GLCCI1 expression. In isolated cell systems the rs37973 variant is associated with significantly decreased luciferase reporter activity; in pooled data from treatment trials patients with the variant allele have reduced FEV 1 responses to ICS (pooled p=0.0007). Overall, subjects homozygous for the mutant rs37973 allele had only 1/3 the FEV 1 increase on inhaled corticosteroids vs. those homozygous wild type (3.2±1.6% vs. 9.4±1.1%), accompanied by a significantly higher risk of a poor (i.e. lowest quartile) response (OR 2.36, 95% CI: 1.24-4.51), with genotype accounting for ∼6.6% of response variability. Conclusion: A functional GLCCI1 variant is associated with substantial decrements in inhaled glucocorticosteroid response in asthma.