Patients with cystic fibrosis (CF) display a wide range of disease severity, particularly in pulmonary phenotype. Although some of this variability can be attributed to specific mutations within the CFTR gene (allelic heterogeneity), much of this variability has not been adequately explained. The central hypothesis of this proposal is that much of the """"""""severity"""""""" (or """"""""mildness"""""""") of CF lung disease reflects the influence of non-CFTR """"""""modifier"""""""" alleles (genes). This project is designed to identify associations between non-CFTR genes and the pulmonary phenotype. To accomplish this goal, we will study 600 CF patients who have the same CFTR genetic background, i.e., homozygous deltaF508, and who are at the extremes of pulmonary phenotype, i.e., the most severe and mildest lung disease. Pulmonary disease severity (or mildness) will be quantitated by longitudinal lung function analysis with informative censoring. The overall strategy will be to test for the association of candidate modifier alleles (genes) with the severity (or mildness) of - pulmonary disease. Key clinical features (gender; age-at-diagnosis; sweat Cl ; nutrition; and respiratory microbiology) will be important variables in the overall analysis. Initially, we will test candidate genes (n=200) that have been implicated in the pathophysiology of CF lung disease. We will utilize a pooling strategy to expedite the first rounds of testing. After pooling DNA from the """"""""severe"""""""" patients, and pooling DNA from the mild patients, we can identify those genes (alleles) with the greatest association with phenotype. Follow-up genotyping in individual subjects will allow subgroup analyses (gender; age-at-diagnosis; nutrition; respiratory microbiology) for each gene, as well as more complex analyses to search for interaction among different alleles. Subsequent studies will involve genome-wide testing with SNPs to identify loci (and genes) that are not present in the initial list of candidate genes. Identification of genes that modulate the severity of the pulmonary phenotype will improve our understanding of the pathophysiology of CF lung disease, and identify new targets for therapeutic intervention.
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