Text Size
A A A
U. S. Department of Health and Human Services
Skip Navigation

Home > RePORTER > Project Information

Project InformationProject Information Help

Project Number: 3R01CA080127-09S1 Contact PI / Project Leader: YANG, PING
Title: ALPHA-1 AD CARRIERS AND LUNG CANCER RISK Awardee Organization: MAYO CLINIC
Description
Abstract Text:
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.
NIH Spending Category:
Cancer; Chronic Obstructive Pulmonary Disease; Clinical Research; Emphysema; Genetic Testing; Genetics; Lung; Lung Cancer; Prevention; Smoking and Health; Tobacco
Project Terms:
Age-Years; Airway Obstruction; Alleles; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; alpha 1-antitrypsin-leukocyte elastase complex; base; Binding (Molecular Function); Biological Assay; Biological Markers; biomarker; Cancer Etiology; cancer risk; Case-Control Studies; Categories; Chest; Chronic; Chronic Bronchitis; Chronic lung disease; Chronic Obstructive Airway Disease; Cigarette Smoker; Clinical; Clinical assessments; Data; Databases; design; Development; Diagnosis; Diagnostic; Disease; DNA Markers; Doctor of Philosophy; Dose; Early Diagnosis; Elastin; Environment; Enzymes; Epidemiologic Methods; Equilibrium; Evaluation; Family Cancer History; Family history of; Gene Frequency; gene interaction; General Population; Genes; Genomics; Genotype; Goals; Grant; high risk; Histologic; Host Defense Mechanism; Human; Indium; Individual; Inflammation; Isoelectric Focusing; Lead; Leukocyte Elastase; Literature; Lung; Lung diseases; Malignant neoplasm of lung; Malignant Neoplasms; Measures; Modeling; Molecular Genetics; Nucleotides; Odds Ratio; oxidation; Pathologic; Pathology; Pathway interactions; Phenotype; Physiological; Polymorphic Microsatellite Marker; Population; Population Attributable Risks; programs; Progress Reports; Protease Inhibitor; Protein C Inhibitor; Pulmonary Emphysema; Recording of previous events; Research; Research Personnel; Resources; Respiratory System; Respiratory tract structure; Risk; Risk Factors; Risk Reduction; Role; Scanning; Screening for Lung Cancer; Serine Protease; Serine Proteinase Inhibitors; Siblings; Smoker; smoking cessation; Specific qualifier value; Spirometry; Staging; Stratification; Structure; Structure of parenchyma of lung; Subgroup; System; Testing; Tissues; Tobacco smoke; tool; transmission process; Variation (Genetics); X-Ray Computed Tomography; Yang



The RePORTER database is available to all public users at http://exporter.nih.gov/. As the data are available for bulk download, the RePORTER system reserves the right to block IP addresses that fail to adhere to instructions in the system’s robots.txt files or submit requests at a rate that negatively impacts service delivery to other users. RePORTER reserves the right to terminate any automated query to the RePORTER application that negatively affects service delivery to other users.

Page Last Updated on February 17, 2013
This site is best viewed with Internet Explorer (7.0 or higher) or Mozilla Firefox (3.0).

NIH...Turning Discovery Into Health®
RePORTER