Alpha₁-antitrypsin deficiency carriers, tobacco smoke, chronic obstructive pulmonary disease, and lung cancer risk

Background: Genetic susceptibility in lung cancer risk has long been recognized but remains ill defined, as does the role of tobacco smoke exposure and chronic obstructive pulmonary disease (COPD). Methods: Using a dual case-control design, we tested whether alpha1-antitrypsin deficiency (α₁ATD) carriers are predisposed to a higher risk of lung cancer, adjusting for the effects of tobacco smoke exposure and COPD. A total of 1856 patients with incident lung cancer were included in the study; 1585 community residents served as controls. A second control group was composed of 902 full siblings of the patients. We first modeled 1585 case-control pairs without the α₁ATD variable using multiple logistic regression analysis and then modeled the α₁ATD allele type in the presence of other known risk factors of lung cancer. Results: We found a significantly increased lung cancer risk among α₁ATDcarriers from 2 parallel case-control comparisons: when patients were compared with unrelated controls, α₁ATD carriers had a 70% higher risk of developing lung cancer than noncarriers (odds ratio, 1.7; 95% confidence interval, 1.2-2.4). In a further comparison of patients with their cancer-free siblings, we found a 2-fold increased lung cancer risk in α₁ATDcarriers (95% confidence interval, 1.4-2.7). Stratified analysis by tumor histologic subtypes showed a significant increase for adenocarcinoma and squamous cell carcinoma among α₁ATD carriers. Conclusion: Our results suggest that α₁ATD carriers are at a 70% to 100% increased risk of lung cancer and may account for 11% to 12% of the patients with lung cancer in our study.