Combined pharmacogenetic effect of ADCY9 and ADRB2 gene polymorphisms on the bronchodilator response to inhaled combination therapy

• Published in: Journal of clinical pharmacy and therapeutics Vol. 36; no. 3; pp. 399 - 405
• Main Authors: Kim, S. H., Ye, Y. M., Lee, H. Y., Sin, H. J., Park, H. S.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.06.2011; Blackwell; Hindawi Limited
• Subjects: adenylyl cyclase type 9; Adenylyl Cyclases - genetics; Administration, Inhalation; Adrenergic beta-2 Receptor Agonists - administration & dosage; Adrenergic beta-2 Receptor Agonists - metabolism; Adrenergic beta-2 Receptor Agonists - therapeutic use; Adult; asthma; Asthma - drug therapy; Asthma - metabolism; Asthma - physiopathology; Biological and medical sciences; Bronchodilator Agents - administration & dosage; Bronchodilator Agents - metabolism; Bronchodilator Agents - therapeutic use; bronchodilator response; Budesonide - administration & dosage; Budesonide - metabolism; Budesonide - therapeutic use; Chronic obstructive pulmonary disease, asthma; Drug Therapy, Combination; Ethanolamines - administration & dosage; Ethanolamines - metabolism; Ethanolamines - therapeutic use; Female; Formoterol Fumarate; gene polymorphism inhaled corticosteroid; Genetic Association Studies; Glucocorticoids - administration & dosage; Glucocorticoids - metabolism; Glucocorticoids - therapeutic use; Humans; Linkage Disequilibrium; long-acting β2-agonist; Male; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Pneumology; Polymorphism, Genetic; Receptors, Adrenergic, beta-2 - genetics; Republic of Korea; Respiratory System - drug effects; Respiratory System - physiopathology; Retrospective Studies; Severity of Illness Index; Republic of Korea; Lung disease; Corticosteroid; Agonist; Drug combination; Pharmacogenetics; Genetic variability; Enzyme; Respiratory disease; Bronchodilator; Phosphorus-oxygen lyases; Genotype; Lyases; adenylyl cyclase type 9; Asthma; Inhalation; Adenylate cyclase; long-acting β2-agonist; gene polymorphism inhaled corticosteroid; Genetics; Bronchus disease; bronchodilator response; Combined treatment; Obstructive pulmonary disease
• ISSN: 0269-4727; 1365-2710
• DOI: 10.1111/j.1365-2710.2010.01196.x

Summary What is known and 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. Materials and 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 (FEV1) 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 FEV1 (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 FEV1 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 FEV1 after 8 and 12 weeks of therapy (P = 0·002 and P = 0·027 respectively). What is new and conclusion:  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.