SLC9A3 – Modifier of Cystic Fibrosis Phenotypes

SLC9A3 encodes the intestinal brush-border Na+/H+ exchanger NHE3, which colocalizes with CFTR at the apical plasma membrane and participates in electrolyte and fluid absorption. Common variants in SLC9A3 have been investigated as modifiers of cystic fibrosis (CF)–related phenotypes, particularly meconium ileus and lung disease severity. These studies leverage large cohorts of CF patients and genome-wide association framework informed by CFTR biology.

A hypothesis-driven GWAS in 3,763 CF patients identified an association between SLC9A3 SNPs and meconium ileus as part of a joint test of 155 apical membrane genes (P = 0.0002) (PMID:22466613). This association was replicated in an independent cohort of 2,372 CF patients with meconium ileus (P = 0.022) (PMID:22466613), demonstrating consistency across unrelated probands and cohorts.

Meta-analysis of lung disease severity in 6,365 CF patients identified a genome-wide significant modifier locus at chr5p13 containing SLC9A3 (P = 6.8 × 10⁻¹²) (PMID:26417704). This locus was one of five robust modifier regions influencing pulmonary phenotype, indicating pleiotropic effects of SLC9A3 variants across CF organ systems.

In a study of 164 CF patients, interactions between CFTR mutations and the SLC9A3 variant rs17563161 were associated with pancreatic insufficiency (P = 0.015) (PMID:29635781). However, in cohorts measuring newborn screening immunoreactive trypsinogen levels (n = 228 total across Colorado, Wisconsin, and France), no SLC9A3 SNPs were associated with prenatal exocrine pancreatic damage (all P > 0.05) (PMID:25771386), suggesting phenotype-specific modifier effects.

No Mendelian segregation of SLC9A3 variants has been observed in families; the modifier effect appears additive and best explained by common-variant mechanisms. Functional studies outside the CF context show that SLC9A3 missense variants such as c.1421G>A (p.Arg474Gln) can reduce NHE3 transporter activity and alter regulatory interactions, but CF-specific functional data are lacking.

Integration of genetic association data supports a Strong category for the SLC9A3–cystic fibrosis modifier relationship, with replicated associations in >6,000 individuals and robust P-values. Genetic evidence is Moderate given reliance on common variant GWAS designs. Functional evidence is Limited in the CF context. Key take-home: SLC9A3 genotyping may inform risk stratification for meconium ileus and lung severity and guide therapeutic development in CF.

References

• Nature genetics • 2012 • Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis. PMID:22466613
• Nature communications • 2015 • Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis. PMID:26417704
• Pediatric pulmonology • 2018 • Interaction among variants in the SLC gene family (SLC6A14, SLC26A9, SLC11A1, and SLC9A3) and CFTR mutations with clinical markers of cystic fibrosis. PMID:29635781
• The Journal of pediatrics • 2015 • Variants in Solute Carrier SLC26A9 Modify Prenatal Exocrine Pancreatic Damage in Cystic Fibrosis. PMID:25771386

Evidence Based Scoring (AI generated)