Cystic fibrosis (CF), an important cause of fatal lung disease in children and young adults, results from genetic deficiency of the CF transmembrane regulator (CFTR). A striking aspect of this disorder is the variability of its lung phenotype: some individuals with CFTR alleles ordinarily associated with severe lung disease (e.g., deltaF508 homozygous) may have only minimal lung disease even in later adulthood. Understanding factors that influence this variability may provide important insights into CF lung disease. A key function of CFTR is to regulate the epithelial sodium channel (ENaC), a major determinant of airway surface hydration. In the setting of CFTR deficiency, excessive sodium absorption via ENaC results in dehydration of airway surface liquid and overlying mucus, impairment of ciliary function, and adhesion of mucus plaques that become a nidus for infection by opportunistic pathogens. Recently, additional ENaC regulators have been identified that represent compelling candidates as modifiers of the CF lung phenotype. Variants of these ENaC regulators may ameliorate mucociliary clearance and result in milder lung disease.
The specific aims of this project are: (1) to screen for functional variants of ENaC regulatory genes in individuals with CF, and (2) to evaluate the relationship between ENaC regulator variants and CF lung phenotypes. Variations in ENaC regulatory genes will be sought in two groups of deltaF508 homozygous subjects, one with severe CF lung disease and the other with CF but minimal lung disease. ENaC regulatory genes will be re-sequenced for these subjects to identify variants. Statistical genetic methods will then be used to analyze the association of allele, genotype, and haplotype frequencies of these variants with median values of age- and height-adjusted FEV1 (primary outcome) and measures of airway infection susceptibility secondary outcomes). Identifying ENaC regulatory genes as modifiers of the CF lung phenotype would provide important insights into disease pathogenesis and define novel targets for therapeutic intervention.
| Bartlett, Jaclyn R; Friedman, Kenneth J; Ling, Simon C et al. (2009) Genetic modifiers of liver disease in cystic fibrosis. JAMA 302:1076-83 |
