title: Effect of β2-adrenergic receptor gene (ADRB2) 3' untranslated region polymorphisms on inhaled corticosteroid/long-acting β2-adrenergic agonist response.
abstract: BACKGROUND
  Evidence suggests that variation in the length of the poly-C repeat in the 3' untranslated region (3'UTR) of the β2-adrenergic receptor gene (ADRB2) may contribute to interindividual variation in β-agonist response. However, methodology in previous studies limited the assessment of the effect of sequence variation in the context of poly-C repeat length. The objectives of this study were to design a novel genotyping method to fully characterize sequence variation in the ADRB2 3'UTR poly-C repeat in asthma patients treated with inhaled corticosteroid and long-acting β2-adrenergic agonist (ICS/LABA) combination therapy, and to analyze the effect of the poly-C repeat polymorphism on clinical response.
  
  
  METHODS
  In 2,250 asthma patients randomized to treatment with budesonide/formoterol or fluticasone/salmeterol in a six-month study (AstraZeneca study code: SD-039-0735), sequence diversity in the ADRB2 poly-C repeat region was determined using a novel sequencing-based genotyping method. The relationship between the poly-C repeat polymorphism and the incidence of severe asthma exacerbations, and changes in pulmonary function and asthma symptoms from baseline to the average during the treatment period, were analyzed.
  
  
  RESULTS
  Poly-C repeat genotypes were assigned in 97% (2,192/2,250) of patients. Of the 13 different poly-C repeat alleles identified, six alleles occurred at a frequency of >5% in one or more population in this study. The repeat length of these six common alleles ranged from 10 to 14 nucleotides. Twelve poly-C repeat genotypes were observed at a frequency of >1%. No evidence of an association between poly-C repeat genotype and the incidence of severe asthma exacerbations was observed. Patients' pulmonary function measurements improved and asthma symptoms declined when treated with ICS/LABA combination therapy regardless of poly-C repeat genotype.
  
  
  CONCLUSIONS
  The extensive sequence diversity present in the poly-C repeat region of the ADRB2 3'UTR did not predict therapeutic response to ICS/LABA therapy.
authors.affiliation: Wake Forest University Health Sciences, Medical Center Blvd, Winston-Salem, NC, 27157, USA. ebleeck@wfubmc.edu.
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Ambrose
authors.forename: Rachael M
authors.initials: RM
authors.lastname: Lawrance
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Cresswell
authors.forename: Mitchell
authors.initials: M
authors.lastname: Goldman
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*; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage*; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage*; D000328:Adult; D001249:Asthma / Q000188:drug therapy / Q000235:genetics*; D001483:Base Sequence; D001993:Bronchodilator Agents / Q000008:administration & dosage; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic / Q000235:genetics*; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D020080:Tandem Repeat Sequences / Q000235:genetics; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D020413:3' Untranslated Regions; C553443:ADRB2 protein, human; D000305:Adrenal Cortex Hormones; D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D018343:Receptors, Adrenergic, beta-2