SLC26A9 – Modifier of Cystic Fibrosis Phenotypes

SLC26A9 encodes an epithelial chloride–bicarbonate exchanger expressed in airway, pancreatic ductal, and intestinal epithelia. Genome-wide association in 3,763 cystic fibrosis patients identified common SNPs at the SLC26A9 locus strongly associated with meconium ileus susceptibility (minimum P = 9.88×10^–9 at rs4077468) (PMID:22466613). These associations were replicated in an independent cohort of 2,372 affected individuals (PMID:22466613). A parallel GWAS in 3,059 individuals with CF revealed a significant association between SLC26A9 variants and cystic fibrosis–related diabetes onset (hazard ratio 1.38; P = 3.6×10^–8), with replication in 694 cases (P = 0.007) (PMID:23670970).

Rare coding variants in SLC26A9 have been implicated in rapidly progressing CF phenotypes. Exome sequencing of six homozygous ΔF508 CF patients with rapid disease progression identified two missense variants—c.229G>A (p.Gly77Ser) in two patients and c.1885C>T (p.Pro629Ser) in one—enriched compared to 3,076 controls (PMID:38852790). These variants localize to conserved transmembrane and STAS domains critical for ion transport function.

Functional assays in Xenopus oocytes demonstrate that the STAS-domain mutation p.Leu683Pro markedly reduces chloride transport and attenuates SLC26A9-mediated enhancement of CFTR function (PMID:21439353). Additional nonsynonymous variants—such as p.Val622Leu and p.Val744Met—exhibit decreased surface expression and transport currents (PMID:22544634). Structural modeling further supports deleterious effects of the p.Gly77Ser and p.Pro629Ser substitutions on the anion transport pore architecture (PMID:38852790).

Clinically, SLC26A9 genotype influences key CF complications: carrier status of risk alleles at rs7512462 modifies sweat chloride concentration and prenatal exocrine pancreatic damage measured by immunoreactive trypsinogen. Although one study found no association of rs7512462 with lung disease severity or ivacaftor response in G551D patients (PMID:33674211), overall data affirm SLC26A9’s role in CF phenotype variability.

Collectively, genetic and functional data support a Moderate level of evidence that SLC26A9 variants modify cystic fibrosis severity. Emerging rare variant discovery and in vitro functional concordance underscore its potential as a therapeutic target. Key take-home: SLC26A9 is a clinically actionable modifier of cystic fibrosis complications, informing risk stratification and precision therapy.

References

• Nature genetics • 2012 • Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis. PMID:22466613
• Diabetes • 2013 • Genetic modifiers of cystic fibrosis-related diabetes. PMID:23670970
• Clinica chimica acta • 2024 • The solute carrier family 26 member 9 modifies rapidly progressing cystic fibrosis associated with homozygous F508del CFTR mutation. PMID:38852790
• Biochimica et biophysica acta • 2011 • Characterization of the L683P mutation of SLC26A9 in Xenopus oocytes. PMID:21439353
• Human mutation • 2012 • Functional analysis of nonsynonymous single nucleotide polymorphisms in human SLC26A9. PMID:22544634
• Journal of cystic fibrosis • 2021 • SLC26A9 SNP rs7512462 is not associated with lung disease severity or lung function response to ivacaftor in cystic fibrosis patients with G551D-CFTR. PMID:33674211

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