Transcriptional Profiling of the Nasal Epithelium in Cystic Fibrosis

Cystic fibrosis (CF), the most common lethal autosomal-recessive disease in the United States (1/3500 newborns), is caused by mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes the CFTR protein, an anion channel expressed in secretory epithelial cells including the airway epithelium. Around 90% of patients with CF have an in-frame deletion of a triplet encoding phenylalanine at position 508 (F508del) on at least one chromosome, leading to ineffective protein folding and trafficking. More than 2000 CFTR sequence variations have been reported, and many of these disease causing genotypes have been classified by their effect on the CFTR synthesis, trafficking, or function [1]. Pulmonary disease is the main cause of morbidity and mortality in CF. Although CF is a monogenetic disease, the correlation between a CFTR genotype and severity of pulmonary disease is poor [2]. The R117H mutation in particular has a wide range of disease expression [3]. Mechanisms for the disparity between genotype and phenotype are poorly understood. Modifier genes, environmental factors and epigenetic changes are likely contributors to the disease severity. Previous studies suggest a substantial role for additional genetic influences, known as “CF modifiers” [4-6]. Polymorphisms in a handful of genes have been associated with the genotype-phenotype discrepancy, including mannose-binding lectin 2 (MBL2) and transforming growth factor beta 1 (TGFβ1). [7, 8] It is anticipated that there are other CF modifying genes that remain to be discovered, as well as contributions from environment and epigenetics changes [9]. It is likely that the impact of these influences may be reflected in gene expression analysis. Two small molecular modulators of the mutant CFTR channel have been approved by the FDA, and have been determined to improve protein folding and trafficking (VX809, or lumacaftor) or restore CFTR channel current (VX770, or ivacaftor), a