CFTR Gene Modifiers

Cystic fibrosis (also known as CF, mucovoidosis, or mucoviscidosis) is a hereditary disease affecting the exocrine (mucus) glands of the lungs, liver, pancreas, and intestines, causing progressive disability due to multisystem failure. There is no cure for CF and the population of cystic fibrosis patients is growing, as the majority of pediatric patients are now living well into adulthood. In fact, there are many people with cystic fibrosis who may now anticipate a normal life span. In the United States, 1 in 3,900 children are born with. It is most common among western European populations and Ashkenazi Jews; one in twenty-two people of Mediterranean descent are carriers of one gene for CF, making it the most common genetic disease in these populations. Dr. Hardiman's native country Ireland has the highest rate of CF carriers in the world (1 in 19).

We have applied applying genomic approaches to study a series of cystic fibrosis pulmonary gene modifiers. Collaborative work with Dr. Doug Conrad, Director, UCSD Adult Cystic Fibrosis and Dr. Antine Stenbit at the Medical University of South Carolina has undertaken a specific bench to clinic translational focus centering on aminoglycoside ototoxicity in CF Patients. The reason for this was two-fold. Firstly, aminoglycosides, including tobramycin and gentamicin are the cornerstones of anti-infective therapy of cystic fibrosis patients yet cause undesirable side effects. One such effect is auditory ototoxicity, which is often irreversible and results from long-term repetitive exposure to these powerful antibiotics. Secondly, aminoglycoside ototoxicity has a strong genetic susceptibility.

To date we have focused on the mitochondria. We estimated the frequency of polymorphisms in mitochondrial 12S rRNA that are associated with aminoglycoside ototoxicity and noted several of these occurred at higher frequencies than expected and were associated with clinically significant cases of hearing loss. In the population studied, both patients possessing an A1555G transition exhibited profound ototoxicity after non-toxic dosing of tobramycin. In the course of this study we also identified new homoplasmic genetic variations in the mitochondrial 12S rRNA gene. Several of these newly described variants were observed in highly conserved regions of the gene and were identified in patients with moderate to severe ototoxicity following exposure to aminoglycosides.

The immediate impact of this study is that it helps stratify CF patients, based on risk, into groups that may need more intensive audiometric monitoring or even non-aminoglycoside therapy where clinically appropriate. Ongoing work is taking a candidate gene approach to better understand the genetic basis of ototoxicity.