Genetic modifiers of cystic fibrosis pulmonary disease

Cystic fibrosis (CF) is a common, phenotypically variable disease caused by mutations in the CFTR gene, which encodes a cAMP-dependent chloride channel found in many cell types. Symptoms are primarily gastrointestinal and pulmonary in nature, with the pulmonary disease accounting for the majority of the mortality in CF. A great deal of effort has been dedicated toward the characterization of the genetic contribution to the disease variance, with many modifier genes for cystic fibrosis having been described. We have undertaken a novel approach to the identification of cystic fibrosis modifier genes by establishing the Gene Modifier Study (GMS), which utilizes a candidate gene approach to compare the genetic profile of the most severe CF patients to that of the most mild CF patients. Transforming growth factor beta-1 (TGF-a1), beta-2 adrenergic receptor (ADRB2) and endothelin receptor type A (EDNRA) are candidate CF modifiers described here.;Variants within the TGF-a1 promoter and codon 10 demonstrated a nominal association with CF severity, though the mechanism behind this association has not been elucidated. Variants within ADRB2 associated with CF patient response to inhaled bronchodilators, but not with long-term disease severity and survival.;One of the genes that has shown reproducible genetic association with CF phenotype, is the EDNRA gene. EDNRA binds endothelin-1 (ET-1) in airway smooth muscle cells to stimulate smooth muscle contraction and cell proliferation. Variants within the 3' untranslated region and 5'untranslated region of this gene demonstrated a significant association with pulmonary function levels particularly in females. The combined haplotype between the two positions was a strong predictor of CF severity in females. In follow-up studies performed on primary human tracheal smooth muscle cells, we discovered that the alleles associating with worse CF pulmonary disease, were also found to be associated with increased mRNA message levels, and increased cell proliferation rates.;There are FDA-approved pharmaceutical blockers of EDNRA indicated for the treatment of pulmonary hypertension, thus it is our hope that clinical application of these findings could move rapidly.