Alpha1-antitrypsin and neutrophil elastase imbalance and lung cancer risk.
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


METHODS
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.
Yang
Ping
P
Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA. yang.ping@mayo.edu
Bamlet
William R
WR
Sun
Zhifu
Z
Ebbert
Jon O
JO
Aubry
Marie-Christine
MC
Krowka
Michael J
MJ
Taylor
William R
WR
Marks
Randolph S
RS
Deschamps
Claude
C
Swensen
Stephen J
SJ
Wieben
Eric D
ED
Cunningham
Julie M
JM
Melton
Lee Joseph
LJ
de Andrade
Mariza
M
D000368:Aged; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D019272:Leukocyte Elastase / Q000235:genetics / Q000378:metabolism*; D016015:Logistic Models; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000378:metabolism*; D019896:alpha 1-Antitrypsin Deficiency / Q000150:complications / Q000235:genetics*
D000515:alpha 1-Antitrypsin; D019272:Leukocyte Elastase