IL-4 receptor polymorphisms predict reduction in asthma exacerbations during response to an anti-IL-4 receptor α antagonist

Background: This is the first large pharmacogenetic investigation of the inflammatory IL-4/IL-13 pathway in patients with moderate-to-severe asthma. We analyzed genomic DNA from participants in a 12-week placebo-controlled efficacy trial of pitrakinra (1, 3, or 10 mg twice daily), a novel IL-4/IL-13 pathway antagonist (Clinicaltrials.gov NCT00801853). Objectives: The primary hypothesis for this analysis is that amino acid changes in the 3′ end of the IL-4 receptor α gene (IL4RA) or closely proximal variants would predict reductions in asthma exacerbations for subjects randomized to pitrakinra therapy. Methods: Nineteen IL4RA single nucleotide polymorphisms (SNPs) were tested in 407 non-Hispanic white subjects for association with the primary clinical end point of asthma exacerbations and changes in secondary end points for asthma symptom scores. Results: The most consistent pharmacogenetic associations were observed for the correlated tagging SNPs rs8832 and rs1029489 in the IL4RA 3′ untranslated and proximal regions, respectively. Subjects homozygous for the rs8832 common G allele randomized to pitrakinra (placebo group nonsignificant) had decreased asthma exacerbations and decreased nocturnal awakenings and activities limited by asthma. There was also a significant pitrakinra dose-response relationship (placebo/1 mg/3 mg/10 mg) for exacerbations in subjects homozygous for the common allele in rs1029489 (P =.005) and rs8832 (P =.009) and the intronic SNPs rs3024585, rs3024622, and rs4787956 (P =.03). Conclusion: This study demonstrates a significant pharmacogenetic interaction between anti-IL-4 receptor α therapy and IL4RA gene variation, identifying an asthma subgroup that is more responsive to therapy with this antagonist.