Chronic obstructive pulmonary disease (COPD) is a disease of tremendous public health concern. Cigarette smoking is the major environmental risk for disease, but the development of airflow obstruction is variable amongst smokers. COPD is likely a genetically complex disease, but alpha 1-antitrypsin (AAT) deficiency is the only known genetic risk factor for COPD. Variability in lung function decline also exists among individuals with severe AAT deficiency (genotype PI ZZ), suggesting the presence of other genetic factors relevant to disease development and progression. A subset of individuals with COPD will also have manifestations of asthma. We hypothesize that genes associated with asthma and asthma-related phenotypes represent modifying factors for the expression of COPD in individuals with severe AAT deficiency. Through the funded NIH project """"""""Genetic Modifiers of Alpha 1-Antitrypsin Deficiency"""""""" (RO1 HL 68926), 400 families are being collected that include at least two adult PI ZZ siblings. We propose to investigate asthma phenotypes and asthma candidate gene polymorphisms in these families, using a candidate gene approach and family-based association tests for analysis, to pursue three distinct hypotheses, 1). We hypothesize that asthma phenotypes are common in PI ZZ AAT deficient individuals, and may be modified by age, sex, and level of lung function. 2) We hypothesize that asthma candidate gene polymorphisms are associated with asthma phenotypes in PI ZZ individuals. 3) We hypothesize that asthma candidate gene polymorphisms are associated with COPD phenotypes in PI ZZ individuals. Family-based association analysis of asthma candidate genes in a population enriched to develop COPD from a major gene effect will be complementary to the ongoing project that uses genome scanning and linkage analysis to identify modifier genes for COPD in this population. Understanding modifying factors for lung disease in individuals with AAT deficiency will potentially have important prognostic and therapeutic impact. The identification of modifying factors of COPD in AAT deficiency may have significant public health relevance to COPD patients without AAT deficiency.
| He, J-Q; Foreman, M G; Shumansky, K et al. (2009) Associations of IL6 polymorphisms with lung function decline and COPD. Thorax 64:698-704 |
| Kim, Woo Jin; Hersh, Craig P; DeMeo, Dawn L et al. (2009) Genetic association analysis of COPD candidate genes with bronchodilator responsiveness. Respir Med 103:552-7 |
| Hunninghake, Gary M; Cho, Michael H; Tesfaigzi, Yohannes et al. (2009) MMP12, lung function, and COPD in high-risk populations. N Engl J Med 361:2599-608 |
| Bhattacharya, Soumyaroop; Srisuma, Sorachai; Demeo, Dawn L et al. (2009) Molecular biomarkers for quantitative and discrete COPD phenotypes. Am J Respir Cell Mol Biol 40:359-67 |
| Castaldi, P J; DeMeo, D L; Kent, D M et al. (2009) Development of predictive models for airflow obstruction in alpha-1-antitrypsin deficiency. Am J Epidemiol 170:1005-13 |
| DeMeo, Dawn L; Mariani, Thomas; Bhattacharya, Soumyaroop et al. (2009) Integration of genomic and genetic approaches implicates IREB2 as a COPD susceptibility gene. Am J Hum Genet 85:493-502 |
| Foreman, M G; DeMeo, D L; Hersh, C P et al. (2008) Polymorphic variation in surfactant protein B is associated with COPD exacerbations. Eur Respir J 32:938-44 |
| Demeo, Dawn L; Campbell, Edward J; Barker, Alan F et al. (2008) IL10 polymorphisms are associated with airflow obstruction in severe alpha1-antitrypsin deficiency. Am J Respir Cell Mol Biol 38:114-20 |
| Demeo, Dawn L; Sandhaus, Robert A; Barker, Alan F et al. (2007) Determinants of airflow obstruction in severe alpha-1-antitrypsin deficiency. Thorax 62:806-13 |
| DeMeo, Dawn L; Hersh, Craig P; Hoffman, Eric A et al. (2007) Genetic determinants of emphysema distribution in the national emphysema treatment trial. Am J Respir Crit Care Med 176:42-8 |
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