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Familial Aggregation of Severe, Early-Onset COPD*: Candidate Gene Approaches

Edwin K. Silverman, MD; Frank E. Speizer, MD, FCCP; Scott T. Weiss, MD, FCCP; Harold A. Chapman, Jr., MD; Austin Schuette; Edward J. Campbell, MD; John J. Reilly, Jr., MD; Leo C. Ginns, MD, FCCP; Jeffrey M. Drazen, MD, FCCP
Author and Funding Information

*From Brigham and Women’s Hospital (Drs. Silverman, Speizer, Weiss, Chapman, Reilly, and Drazen, and Mr. Schuette), Massachussetts General Hospital (Dr. Ginns), and Harvard Medical School (Drs. Silverman, Speizer, Weiss, Chapman, Reilly, Ginns, and Drazen), Boston, MA; and the University of Utah (Dr. Campbell), Salt Lake City, UT.

Correspondence to: Edwin Silverman, MD, Brigham and Women’s Hospital, Harvard Medical School, 181 Longwood Ave, Boston, MA 02115-5804



Chest. 2000;117(5_suppl_1):273S-274S. doi:10.1378/chest.117.5_suppl_1.273S
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Abbreviations: A1AT = α1-antitrypsin; β2AR = β2-adrenergic receptor

Severe α1-antitrypsin (A1AT) deficiency is the only proven genetic risk factor for COPD. Asthmatics may develop chronic airflow obstruction, but it is unknown if asthma and COPD share common genetic determinants. To study novel genetic determinants of COPD, we enrolled 44 severe, early-onset COPD probands (FEV1 < 40%; age, < 53 years, without severe A1AT deficiency) and also obtained DNA samples from 266 of their relatives. Ongoing work in our laboratory has demonstrated increased risk to current or exsmoking first-degree relatives of early-onset COPD probands for reduced FEV1, chronic bronchitis, and spirometric bronchodilator responsiveness. β2-adrenergic receptor (β2AR) polymorphisms have been associated with asthma severity, but the role of variation in the β2AR gene in COPD is unknown. Therefore, we performed linkage analysis and family-based association analysis using the β2AR amino acid 16 polymorphism with categorical phenotypes including the following: mild airflow obstruction (FEV1 < 80%; FEV1/FVC < 90% predicted), moderate airflow obstruction (FEV1 < 60%; FEV1/FVC < 90% predicted), chronic bronchitis, percent bronchodilator responsiveness (FEV1 increase > 10%), and absolute bronchodilator responsiveness (FEV1 increase > 200 mL). Nonparametric linkage analysis was performed with GENEHUNTER; we found no evidence for significant linkage of β2AR amino acid 16 genotype to mild airflow obstruction (p = 0.7), moderate airflow obstruction (p = 0.7), chronic bronchitis (p = 0.5), percent bronchodilator responsiveness (p = 0.4), or absolute bronchodilator responsiveness (p = 0.4). In addition, family-based association studies were performed with the probands and their siblings using the sibship disequilibrium test; no evidence for significant associations between COPD-related phenotypes and β2AR genotype was found. In summary, we found no evidence for significant linkage or association of this B2AR polymorphism to COPD-related phenotypes. Additional investigation in early-onset COPD families is warranted to determine if shared genetic determinants for asthma and COPD can be identified.

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