title: 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).
  
  
  OBJECTIVE
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Slager
authors.forename: Babatunde A
authors.initials: BA
authors.lastname: Otulana
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Hawkins
authors.forename: Yu Ping
authors.initials: YP
authors.lastname: Yen
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Peters
authors.forename: Sally E
authors.initials: SE
authors.lastname: Wenzel
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Meyers
authors.forename: Eugene R
authors.initials: ER
authors.lastname: Bleecker
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics / Q000276:immunology; D000328:Adult; D000483:Alleles; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006720:Homozygote; D006801:Humans; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D053662:Interleukin-4 Receptor alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D010919:Placebos; D020641:Polymorphism, Single Nucleotide / Q000235:genetics* / Q000276:immunology; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D020413:3' Untranslated Regions; D018927:Anti-Asthmatic Agents; C504000:IL4R protein, human; D018793:Interleukin-13; D053662:Interleukin-4 Receptor alpha Subunit; D010919:Placebos; C559987:pitrakinra; D015847:Interleukin-4