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

Arch Intern Med. 2008 May 26;168(10):1097-103. doi: 10.1001/archinte.168.10.1097.


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 alpha(1)-antitrypsin deficiency (alpha(1)ATD) 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 alpha(1)ATD variable using multiple logistic regression analysis and then modeled the alpha(1)ATD allele type in the presence of other known risk factors of lung cancer.

Results: We found a significantly increased lung cancer risk among alpha(1)ATD carriers from 2 parallel case-control comparisons: when patients were compared with unrelated controls, alpha(1)ATD 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 alpha(1)ATD carriers (95% confidence interval, 1.4-2.7). Stratified analysis by tumor histologic subtypes showed a significant increase for adenocarcinoma and squamous cell carcinoma among alpha(1)ATD carriers.

Conclusion: Our results suggest that alpha(1)ATD 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma / genetics*
  • Aged
  • Carcinoma, Squamous Cell / genetics*
  • Case-Control Studies
  • Female
  • Heterozygote
  • Humans
  • Lung Neoplasms / genetics*
  • Male
  • Middle Aged
  • Pulmonary Disease, Chronic Obstructive / genetics*
  • Risk Factors
  • alpha 1-Antitrypsin / genetics*


  • alpha 1-Antitrypsin