Beta2-adrenergic receptor genetic polymorphisms and short-term bronchodilator responses in patients with COPD.

BACKGROUND COPD is characterized by a persistent airflow limitation that is not fully reversible; thus, the reversibility of airflow limitations in response to a bronchodilator is an important component of COPD. Several studies have established that two common nonsynonymous polymorphisms in the beta2-adrenergic receptor gene (ADRB2), Arg16Gly and Gln27Glu, have important effects in modulating responses to beta2-agonists; however, the effects of these polymorphisms on responses to beta2-agonists in patients with COPD is unknown. OBJECTIVE To examine whether different genotypes at these two polymorphisms are related to differential responses to inhaled beta2-agonists in patients with COPD. DESIGN AND PARTICIPANTS A total of 246 patients with COPD who were participants in a longitudinal study of COPD (ie, the Hokkaido COPD cohort study) were studied. We compared short-term bronchodilator responses (BDRs) to salbutamol according to ADRB2 genotypes at codons 16 and 27. RESULTS The presence of the Arg16 allele was associated with lower BDRs to beta2-agonist inhalation. The mean (+/-SD) log (postbronchodilator FEV1-prebronchodilator FEV1) values of Gly16 homozygotes (n=65), Arg16Gly16 heterozygotes (n=106), and Arg16 homozygotes (n=75) were 2.19+/-0.43, 2.09+/-0.42, and 2.01+/-0.42, respectively (p<0.05). The genetic effects of the Arg16Gly polymorphism were independent of the severity of airflow limitation, age, and smoking status. The most common Arg16-Gln27 haplotype was also significantly associated with decreased BDRs to salbutamol (p<0.01). CONCLUSION The genetic effects of ADRB2 gene polymorphisms may explain some of the variability in response to therapeutic doses of a short-acting beta2-agonists in patients with COPD.

[1]  M. Hasegawa,et al.  Characterisation of phenotypes based on severity of emphysema in chronic obstructive pulmonary disease , 2007, Thorax.

[2]  Deborah A Meyers,et al.  Sequence, haplotype, and association analysis of ADRbeta2 in a multiethnic asthma case-control study. , 2006, American journal of respiratory and critical care medicine.

[3]  A. Gulsvik,et al.  Bronchodilator reversibility testing in an adult general population; the importance of smoking and anthropometrical variables on the response to a β2-agonist , 2006 .

[4]  M. Nishimura,et al.  Association between nonspecific airway hyperresponsiveness and Arg16Gly beta2-adrenergic receptor gene polymorphism in asymptomatic healthy Japanese subjects. , 2006, Chest.

[5]  A. Gulsvik,et al.  Post-bronchodilator spirometry reference values in adults and implications for disease management. , 2006, American journal of respiratory and critical care medicine.

[6]  K. Broadley.  Beta-adrenoceptor responses of the airways: for better or worse? , 2006, European journal of pharmacology.

[7]  Vernon M. Chinchilli,et al.  β-Adrenergic Receptor Polymorphisms and Response to Salmeterol , 2006 .

[8]  M. Munakata,et al.  Molecular-Based Haplotype Analysis of the β 2-Adrenergic Receptor Gene (ADRB2) in Japanese Asthmatic and Non-Asthmatic Subjects. , 2006, Allergology international : official journal of the Japanese Society of Allergology.

[9]  N. Anthonisen,et al.  Bronchodilator response in the lung health study over 11 yrs , 2005, European Respiratory Journal.

[10]  E. Silverman,et al.  Pharmacogenetic differences in response to albuterol between Puerto Ricans and Mexicans with asthma. , 2005, American journal of respiratory and critical care medicine.

[11]  E. Israel,et al.  Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial , 2004, The Lancet.

[12]  Naftali Kaminski,et al.  Comprehensive gene expression profiles reveal pathways related to the pathogenesis of chronic obstructive pulmonary disease. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[13]  R. Perng,et al.  Characteristics of airway inflammation and bronchodilator reversibility in COPD: a potential guide to treatment. , 2004, Chest.

[14]  I. Hall,et al.  The arginine-16 beta2-adrenoceptor polymorphism predisposes to bronchoprotective subsensitivity in patients treated with formoterol and salmeterol. , 2003, British journal of clinical pharmacology.

[15]  E. Silverman,et al.  Genome-wide linkage analysis of bronchodilator responsiveness and post-bronchodilator spirometric phenotypes in chronic obstructive pulmonary disease (vol 12, pg 1199, 2003) , 2003 .

[16]  J. Drazen,et al.  β-Agonists and asthma: too much of a good thing? , 2003 .

[17]  B. Kobilka,et al.  Antithetic regulation by β-adrenergic receptors of Gq receptor signaling via phospholipase C underlies the airway β-agonist paradox , 2003 .

[18]  S. Spencer,et al.  Bronchodilator reversibility testing in chronic obstructive pulmonary disease , 2003, Thorax.

[19]  E. Silverman,et al.  Genome-wide linkage analysis of bronchodilator responsiveness and post-bronchodilator spirometric phenotypes in chronic obstructive pulmonary disease. , 2003, Human molecular genetics.

[20]  D. Schaid,et al.  Score tests for association between traits and haplotypes when linkage phase is ambiguous. , 2002, American journal of human genetics.

[21]  T. Niu,et al.  Association of Asthma with β2-Adrenergic Receptor Gene Polymorphism and Cigarette Smoking , 2001 .

[22]  L. Fabbri,et al.  Partial reversibility of airflow limitation and increased exhaled NO and sputum eosinophilia in chronic obstructive pulmonary disease. , 2000, American journal of respiratory and critical care medicine.

[23]  T. Niu,et al.  Familial aggregation of bronchodilator response: a community-based study. , 2000, American journal of respiratory and critical care medicine.

[24]  R S Judson,et al.  Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[25]  E. Silverman,et al.  The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma. , 2000, American journal of respiratory and critical care medicine.

[26]  F. Hargreave,et al.  Sputum eosinophilia predicts benefit from prednisone in smokers with chronic obstructive bronchitis. , 1998, American journal of respiratory and critical care medicine.

[27]  R. Erickson,et al.  Association between genetic polymorphisms of the beta2-adrenoceptor and response to albuterol in children with and without a history of wheezing. , 1997, The Journal of clinical investigation.

[28]  Jurg Ott,et al.  Handbook of Human Genetic Linkage , 1994 .

[29]  S. Green,et al.  A polymorphism of the human beta 2-adrenergic receptor within the fourth transmembrane domain alters ligand binding and functional properties of the receptor. , 1993, The Journal of biological chemistry.

[30]  S. Liggett,et al.  Mutations in the gene encoding for the beta 2-adrenergic receptor in normal and asthmatic subjects. , 1993, American journal of respiratory cell and molecular biology.

[31]  A. Miller,et al.  Lung function testing: selection of reference values and interpretative strategies. , 1992, The American review of respiratory disease.

[32]  C. Sköld,et al.  Smoking cessation rapidly reduces cell recovery in bronchoalveolar lavage fluid, while alveolar macrophage fluorescence remains high. , 1992, Chest.

[33]  A. Buist,et al.  Spirometry in the Lung Health Study. 1. Methods and quality control. , 1991, The American review of respiratory disease.

[34]  Nicklas Ra.  Paradoxical bronchospasm associated with the use of inhaled beta agonists , 1990 .

[35]  D. Postma,et al.  Prognosis of chronic obstructive pulmonary disease: the Dutch experience. , 1989, The American review of respiratory disease.

[36]  J. Kaprio,et al.  Decreased beta-adrenergic receptor density and catecholamine response in male cigarette smokers. A study of monozygotic twin pairs discordant for smoking. , 1988, Circulation.

[37]  G. Guyatt,et al.  Acute response to bronchodilator. An imperfect guide for bronchodilator therapy in chronic airflow limitation. , 1988, Archives of internal medicine.

[38]  H. D. Short,et al.  Bronchodilators in chronic air-flow limitation. Effects on airway function, exercise capacity, and quality of life. , 1987, The American review of respiratory disease.

[39]  N. Anthonisen,et al.  Prognosis in chronic obstructive pulmonary disease. , 1990, The American review of respiratory disease.

[40]  D. Postma,et al.  Assessment of ventilatory variables in survival prediction of patients with chronic airflow obstruction: the importance of reversibility. , 1985, European journal of respiratory diseases.

[41]  B. Nickerson,et al.  Within-subject variability and per cent change for significance of spirometry in normal subjects and in patients with cystic fibrosis. , 2015, The American review of respiratory disease.

[42]  A. Buist,et al.  The effect of smoking cessation on pulmonary function: a 30-month follow-up of two smoking cessation clinics. , 2015, The American review of respiratory disease.