Am. J. Respir. Crit. Care Med., Volume 157, Number 6, June 1998, 1770-1778

Genetic Epidemiology of Severe, Early-onset Chronic Obstructive Pulmonary Disease
Risk to Relatives for Airflow Obstruction and Chronic Bronchitis

EDWIN K. SILVERMAN, HAROLD A. CHAPMAN, JEFFREY M. DRAZEN, SCOTT T. WEISS, BERNARD ROSNER, EDWARD J. CAMPBELL, WALTER J. O'DONNELL, JOHN J. REILLY, LEO GINNS, STEVEN MENTZER, JOHN WAIN, and FRANK E. SPEIZER

Channing Laboratory and Division of Pulmonary and Critical Medicine, Department of Medicine, and Division of Thoracic Surgery, Department of Surgery, Brigham and Women's Hospital; Pulmonary and Critical Care Unit, Department of Medicine, and Division of General Thoracic Surgical Services, Department of Surgery, Massachusetts General Hospital; Harvard Medical School, Boston, Massachusetts; and Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah

Severe alpha-1-antitrypsin deficiency is the only proven genetic risk factor for chronic obstructive pulmonary disease (COPD). We have assembled a cohort of 44 probands with severe, early-onset COPD, who do not have severe alpha-1-antitrypsin deficiency. A surprisingly high prevalence of females (79.6%) was found. Assessment of the risk to relatives of these early-onset COPD probands for airflow obstruction and chronic bronchitis was performed to determine whether significant familial aggregation for COPD, independent of alpha-1-antitrypsin deficiency, could be demonstrated. First- degree relatives of early-onset COPD probands had significantly lower FEV₁ and FEV₁/FVC values than control subjects (p < 0.01), despite similar pack-years of smoking. Reduced spirometric values in first-degree relatives of early-onset COPD probands were found only in current or ex-cigarette smokers. The mean FEV₁ in current or ex-smoking first-degree relatives was 76.1 ± 20.9% predicted compared to 89.2 ± 14.4% predicted in current or ex-smoking control subjects (p < 0.01); in lifelong nonsmokers, the mean FEV₁ was 93.4% predicted for both control subjects and first-degree relatives of early-onset COPD probands. Generalized estimating equations, adjusting for age and pack-years of smoking, demonstrated increased odds of reduced FEV₁ and chronic bronchitis in current or ex-smoking first-degree relatives of early-onset COPD probands. Using a new method to estimate relative risk from relative odds, we estimate that the relative risks for FEV₁ below 60%, FEV₁ below 80%, and chronic bronchitis are each approximately three in current or ex-smoking first-degree relatives of early-onset COPD probands. The increased risk to relatives of early-onset COPD probands for reduced FEV₁ and chronic bronchitis, limited to current or ex-smokers, suggests genetic risk factor(s) for COPD that are expressed in response to cigarette smoking.

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