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Alpha-1-antitrypsin deficiency is a genetic condition associated with severe, early-onset chronic obstructive pulmonary disease (COPD). However, there is significant variability in lung function impairment among persons with the protease inhibitor ZZ genotype. Early identification of persons at highest risk of developing lung disease could be beneficial in guiding monitoring and treatment decisions. Using a multicenter, family-based study sample (2002-2005) of 372 persons with the protease inhibitor ZZ genotype, the authors developed prediction models for forced expiratory volume in 1 second (FEV(1)) and the presence of severe COPD using demographic, clinical, and genetic variables. Half of the data sample was used for model development, and the other half was used for model validation. In the training sample, variables found to be predictive of both FEV(1) and severe COPD were age, sex, pack-years of smoking, bronchodilator responsiveness, chronic bronchitis symptoms, and index case status. In the validation sample, the predictive model for FEV(1) explained 50% of the variance in FEV(1), and the model for severe COPD exhibited excellent discrimination (c statistic = 0.88).

Bronchodilator responsiveness has been associated with a subsequent accelerated decline in forced expiratory volume in one second (FEV1). Therefore, bronchodilator responsiveness and total serum immunoglobulin E(IgE) levels were assessed in 184 adult first-degree relatives of probands with severe early-onset chronic obstructive pulmonary disease (COPD) and a control group.Greater bronchodilator responsiveness was found among current smokers or exsmokers who were first-degree relatives of early-onset COPD probands than in currently or exsmoking controls, expressed as increase in FEV1 as a percentage of baseline (5.88.1 versus 2.95.1%, p<0.01), absolute increase in FEV1 from baseline (120130 versus 60110 mL, p<0.05), and increase in FEV1 as a percentage of the predicted value (3.64.1 versus 2.23.9%, p<0.05). However, elevated total serum IgE levels were not found in first-degree relatives of early-onset COPD probands compared with control subjects.The increased bronchodilator responsiveness among currently smoking/exsmoking first-degree relatives of early-onset COPD probands suggests that these individuals may have enhanced susceptibility to the detrimental effects of cigarette smoking. Eur Respir J 1999; 14: 1009±1014. Chronic obstructive pulmonary disease (COPD), the fourth leading cause of death in the USA [1, 2] and a growing international problem, is strongly associated with cigarette smoking [3]. Even though tobacco use is a well-known risk factor for COPD [4], the development of airflow obstruction in response to smoking is highly variable [5], and it has been postulated that individuals may vary in their genetic susceptibility to COPD [3]. In a previous report on individuals without severe a 1 -antitrypsin deficiency, increased risk of airflow obstruction and chronic bronchitis was found in current smokers and exsmokers who were first-degree relatives of probands with severe early-onset COPD, compared with appropriate control subjects [6]. Thus, the findings of the authors and others [7±13] suggest that familial factors, probably genetic, contribute to the development of COPD.Bronchodilator responsiveness, a physiological response that differs from airway responsiveness to bronchoconstrictors, has been associated with a subsequent accelerated decline in forced expiratory volume in one second (FEV1) [14±17]. Thus, bronchodilator responsiveness may be associated with an increased risk of either acquiring COPD or developing the disease at an earlier age in susceptible individuals who smoke.Higher total serum immunoglobulin E (IgE) levels have previously been demonstrated in first degree relatives of PI Z subjects with COPD than in first-degree relatives of PI Z subjects without COPD [18]. This report presents a comparison of bronchodilator responsiveness and total serum IgE levels in 184 adult first-degree relatives of 44 probands with severe early-onset COPD (without severe a 1 -antitrypsin deficiency) and 83 adult control subjects. Methods Study participantsThe screening and enrolment procedures ...

Background: Cigarette smoking causes accelerated facial wrinkling and predisposes to chronic obstructive pulmonary disease (COPD). However, it has long been recognised that there is a subgroup of susceptible smokers who are at increased risk of developing airflow obstruction. We have tested the hypothesis that there is a common susceptibility for the development of COPD and facial wrinkling in cigarette smokers. Methods: One hundred and forty nine current and ex-smokers were recruited from a family based study of COPD genetics, 68 (45.6%) of whom fulfilled the definition of COPD. 124 (83.2%) had no or minor facial wrinkling (Daniell ,IV) and 25 (16.8%) were wrinkled (Daniell score >IV). Generalised estimating equations were used to adjust for familial correlations between related individuals and the potential confounding effects of age and pack years smoked. Results: Forced expiratory volume in 1 second (FEV 1 ) was significantly lower in those with wrinkles than in those without (mean difference in FEV 1 % predicted 213.7%, 95% CI 227.5 to 0.0, p = 0.05) and facial wrinkling was associated with a substantially increased risk of COPD (adjusted OR 5.0, 95% CI 1.3 to 18.5, p,0.02). The Daniell score correlated with the extent of emphysema on the CT scan (p,0.05) and facial wrinkling was also associated with a greater risk of more extensive emphysema (adjusted OR 3.0, 95% CI 1.0 to 9.3, p = 0.05). Conclusion: Facial wrinkling is associated with COPD in smokers, and both disease processes may share a common susceptibility. Facial wrinkling in smokers may therefore be a biomarker of susceptibility to COPD.

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