MUTATIONAL ANALYSIS OF THE CYSTIC FIBROSIS GENE

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Cystic fibrosis (CF) is the most common fatal genetic disease affecting Caucasian populations. The disease is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR encodes a protein that is part of a superfamily of membrane transport molecules that bind ATP and pump specific molecules out of the cell. More than 250 different mutations have been characterized in the CFTR gene, and these mutations account for 80-90% of the disease alleles in most populations. The severity of pulmonary disease in CF patients is highly heterogeneous. Even in individuals with the same genotype there is extensive variation in the progression of the disease, suggesting that additional genetic and/or environmental factors contribute. Previous work has shown that the course of disease is significantly concordant amongst CF siblings, suggesting that a major genetic factor is present. The focus of this project is to identify the genetic basis of the heterogeneity in CF patients. We have analyzed a cohort of CF patients with mild lung disease for associations with genetic markers for genes involved in the immune response. These patients are compared to a group of patients with severe disease. We have observed an association between the HLA DQA 101 allele and mild disease. In addition, we have observed an association between an allele in the interleukin-1 inhibitor and CF pulmonary disease severity. In each of these cases we are collecting information on additional patients to attempt to confirm these associations.