GENETIC EPIDEMIOLOGY OF SEVERE, EARLY-ONSET CHRONIC OBSTRUCTIVE PULMONARY-DISEASE - RISK TO RELATIVES FOR AIR-FLOW OBSTRUCTION AND CHRONIC-BRONCHITIS

Severe alpha-l-antitrypsin deficiency is the only proven genetic risk factor for chronic obstructive pulmonary disease (COPD). We have assem bled a cohort of 44 probands with severe, early-onset COPD, who do not have severe alpha-l-antitrypsin deficiency. A surprisingly high preva lence of females (79.6%) was found. Assessment of the risk to relative s of these early-onset COPD probands for airflow obstruction and chron ic bronchitis was performed to determine whether significant familial aggregation for COPD, independent of alpha-l-antitrypsin deficiency, c ould be demonstrated. First-degree relatives of early-onset COPD proba nds had significantly lower FEV1 and FEV1/FVC values than control subj ects (p < 0.01), despite similar pack-years of smoking. Reduced spirom etric values in first-degree relatives of early-onset COPD probands we re found only in current or ex-cigarette smokers. The mean FEV1 in cur rent 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 earl y-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 rel atives of early-onset COPD probands. Using a new method to estimate re lative risk from relative odds, we estimate that the relative risks fo r FEV1 below 60%, FEV1 below 80%, and chronic bronchitis are each appr oximately three in current or ex-smoking first-degree relatives of ear ly-onset COPD probands. The increased risk to relatives of early-onset COPD probands for reduced FEV1 and chronic bronchitis, limited to cur rent or ex-smokers, suggests genetic risk factor(s) for COPD that are expressed in response to cigarette smoking.