Clarification of the Risk of Chronic Obstructive Pulmonary Disease in α1-Antitrypsin Deficiency PiMZ Heterozygotes

• Published in: American journal of respiratory and critical care medicine Vol. 189; no. 4; pp. 419 - 427
• Main Authors: MOLLOY, Kevin, HERSH, Craig P, MORRIS, Valerie B, CARROLL, Tomás P, O'CONNOR, Catherine A, LASKY-SU, Jessica A, GREENE, Catherine M, O'NEILL, Shane J, SILVERMAN, Edwin K, MCELVANEY, Noel G
• Format: Journal Article
• Language: English
• Published: New York, NY American Thoracic Society 15.02.2014
• Subjects: Adult; Aged; alpha 1-Antitrypsin - genetics; alpha 1-Antitrypsin Deficiency - complications; alpha 1-Antitrypsin Deficiency - genetics; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Biological and medical sciences; Chronic obstructive pulmonary disease, asthma; Errors of metabolism; Female; Forced Expiratory Volume; Gene-Environment Interaction; Genetic Markers; Heterozygote; Humans; Intensive care medicine; Male; Medical sciences; Metabolic diseases; Middle Aged; Odds Ratio; Original; Phenotype; Pneumology; Proteins and glycoproteins; Pulmonary Disease, Chronic Obstructive - diagnosis; Pulmonary Disease, Chronic Obstructive - etiology; Pulmonary Disease, Chronic Obstructive - physiopathology; Risk Factors; Smoking - adverse effects; Spirometry; Surveys and Questionnaires; Vital Capacity; Lung disease; Intensive care; Respiratory disease; Glycoprotein; Metabolic diseases; Risk; heterozygote; antitrypsin; Enzymopathy; α1-Antitrypsin; Genetic disease; Heterozygosity; α; Risk factor; Bronchus disease; Chronic obstructive pulmonary disease; α1-Antitrypsine deficiency; Resuscitation
• ISSN: 1073-449X; 1535-4970; 1535-4970
• DOI: 10.1164/rccm.201311-1984oc

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