Modulatory effect of the SLC9A3 gene on susceptibility to infections and pulmonary function in children with cystic fibrosis

In cystic fibrosis (CF), CFTR dysfunction leads to salt and water imbalance across airway epithelia, depleted surface liquid layer, and impaired mucociliary clearance. This provides optimal conditions for chronic bacterial infections leading to excessive inflammation and progressive obstructive lung disease. We hypothesized that other epithelial channels affecting salt balance across the airways may play a role in the susceptibility to bacterial infections and modulate severity of CF lung disease. The SLC9A3 gene encoding a Na(+) /H(+) exchanger was demonstrated to be a modifier intestinal disease in a murine model of CF. We examined the potential role of SLC9A3 as a modifier of CF lung disease severity. We analyzed 11 SLC9A3 gene variants for association with age of first Pseudomonas aeruginosa infection and lung function in children with CF. The T allele of an intronic variant in the SLC9A3 gene (rs4957061) was significantly (P = 0.02) associated with earlier acquisition of Pseudomonas infection in a cohort of 1,004 pediatric patients. Analysis of lung function in a subset of these patients (752) revealed that patients homozygous for the T allele had substantially reduced lung function and accelerated rate of decline. Although the functional basis for the modulatory effects of this SLC9A3 variant on CF lung disease remains to be elucidated, altered function of the Na(+) /H(+) exchanger may further deplete the airway liquid surface, thereby enhancing susceptibility to Pseudomonas infections and worsening the severity of lung disease.