IL-4 receptor polymorphisms predict reduction in asthma exacerbations during response to an anti-IL-4 receptor α antagonist
Rebecca E Slager, Babatunde A Otulana, Gregory A Hawkins, Yu Ping Yen, Stephen P Peters, Sally E Wenzel, Deborah A Meyers, Eugene R Bleecker, Rebecca E Slager, Babatunde A Otulana, Gregory A Hawkins, Yu Ping Yen, Stephen P Peters, Sally E Wenzel, Deborah A Meyers, Eugene R Bleecker
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.
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Source: PubMed