GENE MODIFIERS OF CYSTIC FIBROSIS LUNG DISEASE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The genetic disease cystic fibrosis, CF, is caused by partial or complete loss of function of the cystic fibrosis transmembrance conductance regulator (CFTR). The function of CFTR is not entirely clear, although it is agreed that a major function is as an apical chloride channel in epithelial cells. As a clinical disorder, CF displays numerous distinct features, including pulmonary disease, the predominant cause of CF mortality. The CF airway is characterized by a long list of attributes, including thickened secretions, chronic colonization by various bacterial species, excessive inflammation and protease burden, and hyperabsorption of luminal sodium, just to name a few. Not only is it difficult to see how altered chloride channel function can lead to this complex phenotype, other events contribuitng to the pathophysiology are not clear either. As a method to identify processes contributing to the pathophysiology, we have screened a population of 3 groups of CF patients for genomic variants of a large panel of genes. These genes were selected because their products are in pathways suggested to be important in CF pathogenesis or have been shown to associate with other pulmonary diseases (asthma, for example). The study expanded beyond just pulmonary disease, and limited data on growth and nutritional status, meconium ileus, and CF-related diabetes were collected as well. Accordingly, genes involved in the endocrine reguation of growth, obesity, type I and II diabetes, etc. were added to the list of candidate modifiers as well. The goal of this study is to complement an existing study by confirming associations and to begin to elucidate the mechanism by which they modify CF phenotypes. As such, the goal of one project will be to collect a second cohort of patients on which the modifier associations can be tested and to collect additional data relevant to the phenotypes showing assocaitons. This study will also propose to collect probands and their parents so that additional types of analyses can be carried out, such as transmission disequilibrium tests. Progress in haplotype mapping of the human genome should also allow more efficient analyses of haplotype distributions as well. Also, we will follow up the observation that variants in the TGFb1 pathway (TGFb1, TGFBR3 and MADH3) associate with differences in pulmonary function between CF patients. The TGFb1 pathway is complex, expressed in virtually every cell type and affecting a variety of processes of interest to CF. Another project will follow up on the observation that variants of endothelin receptor A (EDNRA) and beta 2-adrenergic receptor (ADRB2), genes that affect smooth muscle contraction, associate with survival of CF patients. The ADRB2 association has been seen in two cohorts of patients and thus this project will focus on understanding the mechanism by which the variants exert their effects on patient outcome.