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

Abstract

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.

Polymorphisms in the lectin pathway genes as a possible cause of early chronic Pseudomonas aeruginosa colonization in cystic fibrosis patients

“…Some studies looked for associations between SNPs and age at first infection of P. aeruginosa [5,29] whereas others looked for the frequency of Pa colonization. Chronic Pa colonization is age-dependent and the majority of cystic fibrosis patients become colonized over time.…”

Loss of SLC9A3 decreases CFTR protein and causes obstructed azoospermia in mice

“…Large-scale genetic studies have indicated that genetic variants of SLC9A3 are associated with early infection, lung infection severity, and susceptibility to meconium ileus in patients with CF [28–31]. However, the association between CBAVD, a mild phenotype of CF, and SLC9A3 is unclear.…”

“…Single nucleotide polymorphisms in SLC9A3 in children with CF are significantly associated with two clinical manifestations, the early infection of Pseudomonas aeruginosa and worsened pulmonary function [28]. Genome-wide association studies have indicated that genetic variants of SLC6A14 , SLC26A9 , and SLC9A3 in patients with CF ( n = 3,763) increased susceptibility to early meconium ileus [29,30].…”

Modifier Gene Studies to Identify New Therapeutic Targets in Cystic Fibrosis

“…further supporting the hypothesis that the inhibition of the SLC9A3 transporter could ameliorate the severity of CF disease. Association analyses in young Canadian CF patients revealed the role of this transporter in the susceptibility to earlier onset of Pseudomonas infections and correlated with the decline of lung function [61]. Furthermore, in the NACGMS GWA study several markers on chromosome 5, spanning several genes including AHRR, EXOC3 and SLC9A3, showed suggestive signal, not reaching genome-wide significance, indicating that additional variants in the SLC9A3 and neighboring genes contribute to the variability of the CF lung disease.…”