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J Allergy Clin Immunol. 2012 Aug;130(2):516-22.e4. doi: 10.1016/j.jaci.2012.03.030. Epub 2012 Apr 26.

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

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  • 1Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.

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.

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

PMID:
22541248
[PubMed - indexed for MEDLINE]
PMCID:
PMC3992925
Free PMC Article
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