Cystic fibrosis is a fatal disease caused by defects in CFTR, a chloride channel that is essential for ion and fluid transport in epithelial tissues. Variability in CF disease course and complications, even in patients with identical CFTR genotypes, indicates that other genetic, environmental, or stochastic (random) factors also contribute. Twin studies have revealed that genetic factors other than CFTR underlie much of the risk for two significant complications of CF: meconium ileus, a severe neonatal intestinal obstruction, and CF-related diabetes, which is correlated with increased CF complications and reduced survival. A genome-wide scan has led to identification of genetic loci likely to be linked to these phenotypes. In this project a candidate gene approach will be used to identify genes within these linkage peaks which modify the risk for CF-related diabetes and meconium ileus. Candidates will be selected based on biological plausibility, using our group's extensive experience in CF pathophysiology. An optimal set of single nucleotide polymorphisms will be identified, and DNA from CF patient families will be genotyped. Genetic association and additional linkage analysis will confirm or exclude each candidate gene, as well as refine the linkage peaks. [unreadable] [unreadable] [unreadable]