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

ABSTRACT: 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).The primary hypothesis for this analysis is that amino acid changes in the 3' end of the IL-4 receptor ? gene (IL4RA) or closely proximal variants would predict reductions in asthma exacerbations for subjects randomized to pitrakinra therapy.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.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).This study demonstrates a significant pharmacogenetic interaction between anti-IL-4 receptor ? therapy and IL4RA gene variation, identifying an asthma subgroup that is more responsive to therapy with this antagonist.

SUBMITTER: Slager RE

PROVIDER: S-EPMC3992925 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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

Slager Rebecca E RE Otulana Babatunde A BA Hawkins Gregory A GA Yen Yu Ping YP Peters Stephen P SP Wenzel Sally E SE Meyers Deborah A DA Bleecker Eugene R ER

The Journal of allergy and clinical immunology 20120426 2

<h4>Background</h4>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).<h4>Objectives</h4>The primary hypothesis for this analysis is that amino acid changes in the 3' end of the IL-4 receptor α gene (IL4RA) or c ...[more]

PMID: 22541248

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Project description:BackgroundA Seasonal Asthma Exacerbation Predictive Index (saEPI) was previously reported based on 2 prior National Institute of Allergy and Infectious Diseases Inner City Asthma Consortium trials.ObjectiveThis study sought to validate the saEPI in a separate trial designed to prevent fall exacerbations with omalizumab therapy.MethodsThe saEPI and its components were analyzed to characterize those who had an asthma exacerbation during the Preventative Omalizumab or Step-Up Therapy for Fall Exacerbations (PROSE) study. We characterized those inner-city children with and without asthma exacerbations in the fall period treated with guidelines-based therapy (GBT) in the absence and presence of omalizumab.ResultsA higher saEPI was associated with an exacerbation in both the GBT alone (P < .001; area under the curve, 0.76) and the GBT + omalizumab group (P < .01; area under the curve, 0.65). In the GBT group, younger age at recruitment, higher total IgE, higher blood eosinophil percentage and number, and higher treatment step were associated with those who had an exacerbation compared with those who did not. In the GBT + omalizumab group, younger age at recruitment, increased eosinophil number, recent exacerbation, and higher treatment step were also associated with those who had an exacerbation. The saEPI was associated with a high negative predictive value in both groups.ConclusionsAn exacerbation in children treated with GBT with or without omalizumab was associated with a higher saEPI along with higher markers of allergic inflammation, treatment step, and a recent exacerbation. Those that exacerbated on omalizumab had similar features with the exception of some markers of allergic sensitization, indicating a need to develop better markers to predict poor response to omalizumab therapy and alternative treatment strategies for children with these risk factors. The saEPI was able to reliably predict those children unlikely to have an asthma exacerbation in both groups.

Dataset Information

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

Publications

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

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