TY - JOUR T1 - Late-breaking abstract: Genome-wide association of <em>GLCCI1</em> with asthma steroid treatment response JF - European Respiratory Journal JO - Eur Respir J VL - 38 IS - Suppl 55 SP - 1871 AU - Kelan Tantisira AU - Jessica Lasky-Su AU - Michishige Harada AU - Amy Murphy AU - Augusto Litonjua AU - Blanca Himes AU - Christoph Lange AU - Ross Lazarus AU - Jody Sylvia AU - Barbara Klanderman AU - Qingling Duan AU - Weiliang Qiu AU - Tomomitsu Hirota AU - Fernando Martinez AU - Dave Mauger AU - Christine Sorkness AU - Stanley Szefler AU - Stephen Lazarus AU - Robert Lemanske AU - Stephen Peters AU - John Lima AU - Yusuke Nakamura AU - Mayumi Tamari AU - Scott Weiss Y1 - 2011/09/01 UR - http://erj.ersjournals.com/content/38/Suppl_55/1871.abstract N2 - 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 FEV1 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 FEV1 responses to ICS (pooled p=0.0007). Overall, subjects homozygous for the mutant rs37973 allele had only 1/3 the FEV1 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. ER -