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(Chest. 2005;128:445-452.)
© 2005 American College of Chest Physicians

{alpha}1-Antitrypsin and Neutrophil Elastase Imbalance and Lung Cancer Risk*

Ping Yang, MD, PhD; William R. Bamlet, MS; Zhifu Sun, MD, PhD; Jon O. Ebbert, MD; Marie-Christine Aubry, MD; William R. Taylor, MS; Randolph S. Marks, MD; Claude Deschamps, MD, TS; Stephen J. Swensen, MD; Eric D. Wieben, PhD; Julie M. Cunningham, PhD; Lee Joseph Melton, MD and Mariza de Andrade, PhD

* From the Divisions of Epidemiology and Cancer Center (Drs. Yang, Sun, and Melton), Biostatistics (Mr. Bamlet and Dr. Andrade), Primary Care Internal Medicine (Dr. Ebbert), Anatomic Pathology (Dr. Aubry), Medical Oncology (Dr. Marks), and General Thoracic Surgery (Dr. Deschamps), the Genotyping Share Resource Laboratory (Mr. Taylor and Dr. Cunningham), the Department of Radiology (Dr. Swensen), and the Biochemistry and Molecular Biology and Genomics Research Center (Dr. Wieben), Mayo Clinic College of Medicine, Rochester, MN.

Correspondence to: Ping Yang, MD, PhD, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905; e-mail: yang.ping{at}mayo.edu

Objective: Imbalance between {alpha}1-antitrypsin and neutrophil elastase is an underlying cause of lung tissue damage that may create a favorable host environment for carcinogenesis. We conducted a case-control study to investigate whether genetic variations indicative of {alpha}1-antitrypsin deficiency (A1ATD) or an excess of neutrophil elastase modify lung cancer risk

Design: The case patients were 305 consecutively identified primary lung cancer patients, and the control subjects were 338 community residents. Protease inhibitor-1 (PI1), encoding {alpha}1-antitrypsin, was typed by an isoelectric focusing assay. Neutrophil elastase-2 (ELA2), encoding neutrophil elastase, was typed by two single-nucleotide polymorphism sites. Multivariable logistic regression models tested the independent and interactive effects of PI1, ELA2, tobacco smoke exposure, COPD, and family history of lung cancer

Results: Sex and ethnicity were comparable between case patients and control subjects, but case patients were more likely to be smokers, and to have a history of COPD, environmental tobacco smoke exposure, and a positive family history of lung cancer. Haplotype analysis indicated an overall strong association between the two ELA2 markers and lung cancer risk. Our best-fitting model showed significant and independent effects of the PI1-deficient allele (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.4 to 3.0) and the ELA2 T-G haplotype (OR, 4.1; 95% CI, 1.9 to 8.9) on lung cancer risk, and an increased risk (OR, 2.6; 95% CI, 2.4 to 2.8) for individuals carrying both a PI1-deficient allele and a G-G haplotype

Conclusions: Genotypes indicative of A1ATD and/or an excess of neutrophil elastase are significantly associated with lung cancer risk. Our findings may provide opportunities to better understand the mechanisms of lung cancer development and risk reduction.

Key Words: {alpha}1-antitrypsin deficiency • chronic obstructive • leukocyte elastase • lung neoplasm • pulmonary disease • tobacco smoking






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Copyright © 2005 by the American College of Chest Physicians.