Grant Number:	3R01CA080127-09S1 Interpret this number
Primary Investigator:	Yang, Ping
Organization:	Mayo Clinic Rochester
Project Title:	Alpha-1 Ad Carriers and Lung Cancer Risk
Fiscal Year:	2009

DESCRIPTION (provided by applicant): Lung cancer provides an ideal paradigm for investigating environment-host-gene interactions. We are conducting a case-control study that integrates traditional epidemiologic methods with genetic and molecular tools to evaluate three major factors in lung cancer etiology: a gene (PI1) responsible for alpha1-antitrypsin deficiency (alpha1-ATD), chronic obstructive pulmonary disease (COPD), and tobacco smoke exposure. Our results support our hypothesis that ATD allele carriers are at a higher risk than non-carriers to develop lung cancer among cigarette smokers and never smokers (odds ratio of 1.8-2.3), independent of the effects of COPD. The expected population attributable risk of lung cancer due to alpha1-ATD alleles is estimated to be 9- 12%. To understand the pathway between alpha1-antitrypsin and lung cancer risk, it is critical to investigate the role of the ELA2 gene that encodes neutrophil elastase, the natural counterpart of alpha1-antitrypsin. Using function-related single nucleotide polymorphic (SNP) markers at ELA2, we now can feasibly measure neutrophil elastase levels indirectly through the SNP genotypes. Therefore, we further hypothesize that individuals' genotype indicative of an imbalance between neutrophil elastase and alpha1-antitrypsin modifies lung cancer risk. In this competing renewal application, we plan to accomplish four aims: 1) examine the role of the ELA2 gene and its interaction with the PI1 allele type in lung cancer risk; 2) validate our results from aim 1 and assess the effect of smoking cessation among heavy smokers; 3) estimate host effects of emphysema +/- chronic bronchitis or airway obstruction on the results obtained from aims 1-2; and 4) explore the effects of selected genes representing inflammation and oxidative pathways on the results obtained from aims 1-3. We designed a two-stage case-control study to first test our hypotheses using a newly established resource of over 1,200 lung cancer cases, 1,200 full sibling controls, and 1,200 unrelated controls. We will then validate our results in a high-risk group of 2,400 heavy smokers, all with complete data to characterize COPD subgroups. Genotyping will be based on function-related polymorphic DNA markers and PI1 alleles will be determined by isoelectric focusing assay. Analyses will include multivariable regression models for case-unrelated control comparisons and sibling transmission disequilibrium tests for case-sibling control comparisons. From this study, we may find an explanation of why smokers develop lung cancer. Positive results may identify useful and feasible biologic markers for assisting lung cancer screening and early detection, may suggest directions for further research on pathogenic mechanisms, and may provide opportunities for lung cancer risk reduction among former smokers and people with existing lung diseases.





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