title: Combined pharmacogenetic effect of ADCY9 and ADRB2 gene polymorphisms on the bronchodilator response to inhaled combination therapy.
abstract: OBJECTIVE
  Inhaled combination therapy composing of long-acting β2-agonist and corticosteroid has been widely applied in the management of asthma, but observed treatment responses vary. The aim of this study was to evaluate the pharmacogenetic effect of the adenylyl cyclase type 9 (ADCY9) gene polymorphism on combination therapy.
  
  
  METHODS
  Eighty-six mild to moderate Korean asthmatics were enrolled in this clinical trial. After the 2-week 'run-in' period, patients received budesonide (an inhaled corticosteroid) and formoterol (long-acting β2-agonist) during the following 12-week active treatment period. Forced expiratory volume in 1 s (FEV(1) ) and maximum mid-expiratory flow (MMEF) levels were measured at all visits as primary outcome. ADCY9 (Ile772Met, 150127 C/T, 150130 C/T, 150397 C/T, 150479 C/T, TTTA (5/4) ) and β2-adrenergic receptor (ADRB2, Arg16Gly) gene polymorphisms were genotyped.
  
  
  RESULTS
  Significant associations were observed between the ADCY9 single nucleotide polymorphisms and percent changes in FEV(1) (Ile772Met T/C, P = 0·030) and MMEF (150397 C/T, P = 0·016) after 8 weeks of combination therapy. Haplotype associations were also observed with respect to percent changes in FEV(1) after 8 weeks of therapy (Ht3[TTCC], P = 0·017). Additive therapeutic effect was observed in those with the ADCY9 Ile772Met and ADRB2 Arg16Gly gene polymorphisms in terms of percent change in FEV(1) after 8 and 12 weeks of therapy (P = 0·002 and P = 0·027 respectively).
  
  
  CONCLUSIONS
  Our results suggest that ADCY9 gene polymorphisms may alone, and in combination with ADRB2 gene polymorphisms, contribute to individual response to combination therapy in mild to moderate asthmatics.
authors.affiliation: Department of Allergy and Rheumatology, Ajou University School of Medicine, Suwon, Korea.
authors.forename: S H
authors.initials: SH
authors.lastname: Kim
authors.forename: Y M
authors.initials: YM
authors.lastname: Ye
authors.forename: H Y
authors.initials: HY
authors.lastname: Lee
authors.forename: H J
authors.initials: HJ
authors.lastname: Sin
authors.forename: H S
authors.initials: HS
authors.lastname: Park
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics*; D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D000328:Adult; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D019819:Budesonide / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D004983:Ethanolamines / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use; D005260:Female; D000068759:Formoterol Fumarate; D056726:Genetic Association Studies; D005938:Glucocorticoids / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D056910:Republic of Korea; D012137:Respiratory System / Q000187:drug effects / Q000503:physiopathology; D012189:Retrospective Studies; D012720:Severity of Illness Index
chemical_list: C553443:ADRB2 protein, human; D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D004983:Ethanolamines; D005938:Glucocorticoids; D018343:Receptors, Adrenergic, beta-2; D019819:Budesonide; D000262:Adenylyl Cyclases; C413923:adenylate cyclase 9; D000068759:Formoterol Fumarate