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Ping Yang, MD, PhD; Zhifu Sun, MD; Michael J. Krowka, MD; Marie-Christine Aubry, MD; William R. Bamlet, MS; Jason A. Wampfler, BS; Stephen N. Thibodeau, PhD; Jerry A. Katzmann, PhD; Mark S. Allen, MD; David E. Midthun, MD; Randolph S. Marks, MD; Mariza de Andrade, PhD

Arch Intern Med. 2008;168(10):1097-1103.

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

Results  We found a significantly increased lung cancer risk among ₁ATD carriers from 2 parallel case-control comparisons: when patients were compared with unrelated controls, ₁ATD 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 ₁ATD 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 ₁ATD carriers.

Conclusion  Our results suggest that ₁ATD 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.

Author Affiliations: Division of Epidemiology and Cancer Center (Drs Yang and Sun) and Divisions of Pulmonary and Critical Care Medicine (Drs Krowka and Midthun), Anatomic Pathology (Dr Aubry), Biostatistics (Messrs Bamlet and Wampfler and Dr de Andrade), Experimental Pathology (Dr Thibodeau), Clinical Biochemistry (Dr Katzmann), General Thoracic Surgery (Dr Allen), and Medical Oncology (Dr Marks), Mayo Clinic, Rochester, Minnesota.