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ß₂-Adrenergic Receptor Genetic Polymorphisms and Short-term Bronchodilator Responses in Patients With COPD^*

^* From the Department of Pulmonary Medicine (Dr. Hizawa) Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan; and First Department of Medicine (Drs. Makita, Nasuhara, Betsuyaku, Itoh, Nagai, Hasegawa, and Nishimura), Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Correspondence to: Masaharu Nishimura, MD, First Department of Medicine, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-Ku, Sapporo 060-8638, Japan; e-mail: ma-nishi{at}med.hokudai.ac.jp

Abstract

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 ß₂-adrenergic receptor gene (ADRB2), Arg16Gly and Gln27Glu, have important effects in modulating responses to ß₂-agonists; however, the effects of these polymorphisms on responses to ß₂-agonists in patients with COPD is unknown.

Objective: To examine whether different genotypes at these two polymorphisms are related to differential responses to inhaled ß₂-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 ß₂-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 ß₂-agonists in patients with COPD.

Key Words: Arg16Gly • ß₂-adrenergic receptor • bronchodilator response • COPD • genetic polymorphism