The Natural History of Gene Expression in the Lung Cells of Non-Smokers, Smokers and Ex-Smokers in Health and Disease
Cigarette smoking is the major risk factor for chronic obstructive pulmonary disease (COPD, commonly known as chronic bronchitis and emphysema). Despite this clear link, only 15-20% of smokers develop COPD suggesting that genetic factors affect the lung's susceptibility to the stress of cigarette smoke. The cells lining the airways (epithelium) and cells that help defend the lung (alveolar macrophages) of smokers develop gene expression changes that are different from that of nonsmokers. In the investigators' previous studies they have demonstrated that there are greater than 200 genes that are responsive to cigarette smoke in these cells. But the investigators do not know whether the gene expression is static or changes as a function of time. Genes that show significant changes over time may be relevant to the progression of the disease. Even though quitting smoking reduces the rate at which the lungs decline, many-smokers still go on to develop COPD. This study will provide insights into the natural history of smoking-related gene expression of the lung cells in health and disease.
Chronic Obstructive Pulmonary Disease (COPD)
|Study Design:||Observational Model: Case Control
Time Perspective: Prospective
|Official Title:||The Natural History of Gene Expression in Lung Cells of Non-Smokers, Smokers, and Ex-Smokers in Health and Disease|
- Evaluate gene expression over time [ Time Frame: 12/31/2013 ] [ Designated as safety issue: No ]To prospectively assess changes in lung cell gene expression over time in healthy nonsmokers, healthy smokers and smokers with COPD. To examine what smoking-induced gene expression changes occur in the lung cells of healthy smokers and COPD smokers over time in response to cessation of smoking.
- Quitters who return to smoking and the effects on gene expression [ Time Frame: 12/31/2012 ] [ Designated as safety issue: No ]In individuals who quit but start smoking again despite the standard smoking cessation therapy, what are the effects on gene expression of returning to smoking. To assess whether baseline gene expression determines what genes rapidly change to a more "normal" expression pattern with smoking cessation. Does having established COPD determine the relative reversibility of the gene expression pattern with smoking cessation compared to healthy smokers.
Biospecimen Retention: Samples With DNA
Subjects will not have more than 550 mL of blood drawn over a period of 8 weeks. Airway epithelium from airway brushing samples and alveolar macrophages from bronchoalveolar lavage is processed to yield high quality RNA. Complimentary DNA (cDNA) is transcribed from the RNA in vitro and the product is hybridized onto gene microarray chips.
|Study Start Date:||December 2009|
|Estimated Study Completion Date:||March 2015|
|Estimated Primary Completion Date:||March 2015 (Final data collection date for primary outcome measure)|
A-Healthy Non smokers
Healthy nonsmokers. Defined as non-smokers by self report and urine cotinine levels consistent with a nonsmoker (urine cotinine <5 ng/mL).
Healthy current smokers. Subjects categorized as healthy according to criteria under "Collection" (#1204012331) protocol.
C-Healthy smoker to quit
Healthy smokers willing to quit. Defined by self-report and urine cotinine levels consistent with an active smoker (urine cotinine >50 ng/mL).
D-Current smoker w. COPD
Current smokers with COPD. COPD as defined by the GOLD criteria and currently smoking as defined by self-report and urine cotinine levels consistent with an active smoker (urine cotinine >50 ng/mL)
E-Current COPD smoker to quit
Current smokers with COPD willing to stop smoking. Subjects have COPD as defined by the GOLD criteria
Cigarette smoke is responsible for the majority of lung cancers and is the major cause of COPD, the fourth leading cause of death in the United States. Despite the well established causal role of cigarette smoking in lung cancer and COPD, only 10-20% of smokers actually develop these diseases. This suggests that there are genetic predisposing factors that place some individuals at greater risk. Our prior work shows that healthy smokers (cigarette smokers with normal history, physical exam, lung function tests and chest x-rays) and smokers with COPD have marked up and down regulation of greater than 200 genes in the small airway epithelium and alveolar macrophages. There is however, a varied response to smoking among individuals, with some individuals abnormally expressing far fewer genes. The focus of this study is to evaluate the hypothesis that the response of the lung cells to the stress of smoking is unique to each individual but is consistent over time. Furthermore, individuals that stop smoking will each have a unique response, but is constant over time for each individual. By defining the patterns of biologic response over time among smoking, ex-smoking and nonsmoking subjects, we will be able to identify common biologic pathways as potential targets for intervention.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00974064
|United States, New York|
|Weill Cornell Medical College and Weill Cornell Medical Center, Department of Genetic Medicine|
|New York, New York, United States, 10065-4870|
|Principal Investigator:||Ronald G. Crystal, M.D.||Weill Medical College of Cornell University|