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Genetic risk factors for chronic obstructive pulmonary disease Wallace, Alison Meghan Rose

Abstract

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality. The worldwide increase in cigarette smoking means that COPD is becoming an even greater health problem and will have an astounding impact on health care costs and services. COPD is often thought of as a self-inflicted disease, however, not all people who smoke develop COPD, and not all patients with COPD are smokers. The pathogenesis of COPD is complex and not fully understood. There is an urgent need to improve present drug therapy. The identification of genetic risk factors for COPD will help elucidate the cellular and molecular mechanisms involved in the disease process and aid in the development of therapeutic regimens that can be tailored on an individual basis. I conducted population-based association studies to see whether alpha- and betadefensins, plasminogen activator inhibitor 1, and tissue-type plasminogen activator polymorphisms influenced smokers' susceptibility to lung function decline in a relatively large population of outbred Caucasian individuals. I failed to find associations between polymorphisms in these four genes with rate of decline in lung function in smokers. In addition, I studied patients undergoing surgical resection for lung carcinoma in order to determine whether promoter polymorphisms in five proteinases produced by alveolar macrophages were related to alveolar macrophage mRNA expression and the development of emphysema. Furthermore, I wanted to determine whether mRNA expression of these five proteinases was related to emphysema. I found that the matrix metalloproteinase 9 C-to-T single nucleotide polymorphism (-1562C→T) significantly influenced matrix metalloproteinase 9 mRNA expression in alveolar macrophages. Matrix metalloproteinase 1 and cathepsin L expression levels in uncultured alveolar macrophages were significantly related to emphysema, and a matrix metalloproteinase 9 CA repeat was significantly related to a qualitative measure of emphysema. Matrix metalloproteinase 1, matrix metalloproteinase 9, and cathepsin L represent interesting biomarkers of COPD and their study may help in the development of therapeutic interventions that are individually tailored to patients needs.

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