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

Abstract

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.govNCT00801853).

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.

Conflict of interest statement

Disclosure of potential conflict of interest: R. E. Slager has received grants from the National Institutes of Health (NIH) and research support from Aerovance. B. A. Otulana and Y. P. Yen are employees of Aerovance. G. A. Hawkins has received research support from Aerovance. S. P. Peters has received research support from the NIH. S. E. Wenzel has consulted for Genentech, and has received research support from Aerovance, GlaxoSmithKline, and Sanofi-Aventis. D. A. Meyers and E. R. Bleecker have consulted for and received research support from Aerovance.

Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Figures

FIG 1

Exacerbations by treatment assignment stratified by IL4RA SNP genotype. There was a significant dose-response trend for treatment response to exacerbations in subjects homozygous for the rs8832GG genotype (A) and the GG genotype in the correlated SNP rs1029489 (B).

FIG 2

IL4RA variants associated with exacerbations. Seven IL4RA SNPs were significantly associated with asthma exacerbations by genotype in participants randomized to 3- and 10-mg doses of pitrakinra. The dashed line indicates overall exacerbation frequency (19.7%) in genotyped non-Hispanic white subjects.

FIG 3

Kaplan-Meier plot for time to exacerbation by treatment assignment for subjects with the rs8832GG genotype. On study day 28, LABAs were withdrawn, and inhaled corticosteroids were stepped down on study days 42 and 56 and stopped completely on day 70. There was a significant difference in time to exacerbation by survival time analysis for subjects with the rs8832GG genotype randomized to 10 mg of pitrakinra compared with placebo. P values are from log-rank tests.

FIG 4

IL4RA polymorphisms predict change in nighttime awakenings caused by asthma. There was a significant dose-response trend for change in nighttime awakenings by treatment assignment (placebo/1 mg/3 mg/10 mg) observed for subjects with the common rs8832GG genotype (A) and participants with the common rs3024622CC genotype (B). There was no significant trend for participants with the minor allele in these SNPs. CFB, Change from baseline.