Role of genetic variation in TGF-beta overactivation in COPD

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DESCRIPTION (provided by applicant): Airway remodeling is a critical pathologic component of COPD and is refractory to current therapies. Exacerbations are more frequent in patients with severe COPD, as is airway remodeling, suggesting that airway remodeling and exacerbations are mechanistically linked. Therapies aimed at reversing or stabilizing airway remodeling have the potential to improve lung function and reduce the frequency of exacerbations. There is considerable variability in the reduction in lung function among smokers with similar smoking exposures suggesting that there are genetic differences in susceptibility to airway remodeling in COPD. Our published and preliminary data implicate the integrin ¿8 subunit (ITGB8), which is a major cell surface TGF-¿ receptor regulating the activity and fibroinflammatory effects of TGF-¿, as a novel candidate gene involved in airway remodeling in COPD. Increased expression of ¿v¿8 is seen in airway fibroblasts of human COPD biospecimens, and here we present preliminary genetic epidemiologic studies showing an association of snp rs9791961, which resides in the 5' flanking region near ITGB8, with COPD. The high-risk genotype is associated with increased expression in primary COPD fibroblasts. The integrin ¿v¿8 (expressed in the lung by fibroblasts, dendritic cells and epithelial cells), is a high affinity receptor for the latncy associated peptide (LAP) of TGF-¿, a multifunctional cytokine that must be activated in order to function. Through interactions with LAP, ¿v¿8 is the major activation mechanism of TGF-¿1 (and ¿3) during development and in airway remodeling, in vivo. ITGB8 interacts with a number of genes in the TGF-¿ pathway and is thus positioned at the center of an epistatic circuit regulating the function of TGF-¿ in airway disease. Here we propose the innovative approach of comprehensive discovery of all common ITGB8 genetic variants by sequencing the ITGB8 genomic locus, performing genetic epidemiologic studies, correlation of genetic variants of ITGB8 with increased expression of ITGB8 in human biospecimens, identification and functional analysis of enhancer/repressor regions of ITGB8, and a final test of ITGB8 genetic variants in susceptibility to airway remodeling using humanized BAC transgenic (Tg) mice. Hypothesis: Genetic variation in ITGB8 leads to increased expression of ¿v¿8 and contributes to airway remodeling in COPD. Overall goal: To identify genetic markers for pharmacogenetic targeting of ¿v¿8 in COPD patients.