Common Genetic Determinants of Asthma and COPD-PROGRAM PROJECT

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Asthma and chronic obstructive pulmonary disease (COPD) are the most common chronic diseases of the lung. The combined health care costs for these conditions approximate $36 billion per year. Genetic approaches offer promise to elucidate genetic causes of these diseases and provide new avenues for their prediction, prevention, and more effective treatment. We seek to find asthma genes, COPD genes and common genetic determinants for asthma and COPD relevant to human disease. Asthma and COPD share many clinical phenotypes. Bronchoconstrictor response, bronchodilator response and level of lung function are shared intermediate phenotypes for airway disease and may be developmentally determined. Asthma and COPD share cigarette smoke exposure as a common environmental determinant. Finally, only a minority of ever-smokers develop COPD, indicating some underlying genetic susceptibility which may well relate to the asthma phenotype. Both disorders have been shown to have a genetic component, suggesting the hypothesis that they could share some genes in common. Project 1: To perform a whole genome association study with the Nlumina Sentrix Human HapSOO BeadChip in the CAMP population to find genes for association with asthma affection status, bronchodilator response, and postbronchodilator FEV1 and FEV1/FVC ratio and attempt to replicate 3072 SNPs in the Sepracor EMGB population. Project 2: Test 100 candidate genes for association with COPD affection status, bronchodilator response, and Post-bronchodilator FEV1, and FEV1/FVC ratio in COPD cases and controls and in early-onset COPD families. Project 3: Phenotype 36 different strains of mice for airway responsiveness and smoking-related COPD phenotypes. We will use these data to create two back- crosses to map QTLs for naive airway resistance at baseline and in response to methacholine (Raw), Airway remodeling with chronic cigarette smoke exposure (airway morphometry and change from baseline Raw), and Emphysema (mean linear intercept) and identify candidate genes for asthma and COPD. Finally, all identified replicated SNPs and genes from all three projects will then be assessed in six human populations in Projects 1 and 2 to determine the overlap of these replicated genes for asthma and COPD. The goal of this PPG is replicated genes for airways disease pointing the way to novel pathobiology and clinical prediction.