THE ROLE OF THE IL4/13 PATHWAY IN THE GENETICS OF ASTHMA SEVERITY

Abstract

T helper 2 (Th2)-related interleukin 4/13 pathway genes have been associated with asthma susceptibility; however the role of these genes in asthma severity has not been explored. We tested single nucleotide polymorphisms (SNPs) in the critical Th2 regulator GATA-binding protein 3 (GATA3) and other Th2 genes for association with baseline lung function, allergic symptoms, and health care utilization in non-Hispanic whites (n=437) and African-American (n=208) asthma patients in the Severe Asthma Research Program (SARP). Linear or ordinal regression models with an additive genetic term were developed to evaluate continuous or multi-level categorical variables. In SARP SNPs in GATA3 SNPs were associated with baseline lung function, including rs1244186, which was replicated in The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study. In SARP whites, GATA3 promoter polymorphisms, most notably rs1244181 [Odds Ratio (OR) 1.7, 95% Confidence Interval (CI) 1.23-2.36], were significantly associated with increasing use of inhaled and oral corticosteroids. GATA3 SNPs were also predictors of increased sinus infections, pollen allergy and SARP atopic asthma cluster phenotypes. This analysis provides evidence that GATA3 may contribute to modulation of baseline lung function, steroid use and atopy in severe asthma.