Clarification of the risk of chronic obstructive pulmonary disease in α1-antitrypsin deficiency PiMZ heterozygotes

Abstract

Rationale: Severe α1-antitrypsin deficiency (typically PiZZ homozygosity) is associated with a significantly increased risk of airflow obstruction and emphysema but the risk of chronic obstructive pulmonary disease (COPD) in PiMZ heterozygotes remains uncertain.

Objectives: This was a family-based study to determine the risk of COPD in PiMZ individuals.

Methods: We compared 99 PiMM and 89 PiMZ nonindex subjects recruited from 51 index probands who were confirmed PiMZ heterozygotes and also had a diagnosis of COPD Global Initiative for Chronic Obstructive Lung Disease stage II-IV. The primary outcome measures of interest were quantitative variables of pre- and post-bronchodilator FEV1/FVC ratio, FEV1 (liters), FEV1 (% predicted), forced expiratory flow midexpiratory phase (FEF25-75; liters per second), FEF25-75 (% predicted), and a categorical outcome of COPD.

Measurements and main results: PiMZ heterozygotes compared with PiMM individuals had a reduced median (interquartile range) post-bronchodilator FEV1 (% predicted) (92.0 [75.6-105.4] vs. 98.6 [85.5-109.7]; P = 0.04), FEV1/FVC ratio (0.75 [0.66-0.79] vs. 0.78 [0.73-0.83]; P = 0.004), and FEF25-75 (% predicted) (63.84 [38.45-84.35] vs. 72.8 [55.5-97.7]; P = 0.0013) compared with PiMM individuals. This effect was abrogated in never-smoking and accentuated in ever-smoking PiMZ individuals. PiMZ heterozygosity was associated with an adjusted odds ratio for COPD of 5.18 (95% confidence interval, 1.27-21.15; P = 0.02) and this was higher (odds ratio, 10.65; 95% confidence interval, 2.17-52.29; P = 0.004) in ever-smoking individuals.

Conclusions: These results indicate that PiMZ heterozygotes have significantly more airflow obstruction and COPD than PiMM individuals and cigarette smoke exposure exerts a significant modifier effect.

Figure 1.

Post-bronchodilator spirometry in ever- and never-smoking individuals. Post-bronchodilator FEV₁/FVC ratio (A), FEV₁ (% predicted) (B), and forced expiratory flow midexpiratory phase (FEF_25–75; % predicted) (C) in ever- versus never-smokers. “Never smoker” was defined as less than 20 packs of cigarettes or 12 oz of tobacco in a lifetime or less than one cigarette a day for 1 year.

Figure 2.

Post-bronchodilator spirometry in low and high cigarette smoke exposure groups. Post-bronchodilator FEV₁/FVC ratio (A), FEV₁ (% predicted) (B), and forced expiratory flow midexpiratory phase (FEF_25–75; % predicted) (C) in low versus high smoke exposure groups. A low exposure was defined as less than 20 pack-years of smoking and a high exposure as greater than or equal to 20 pack-years of smoking.