SLC6A14 – Cystic Fibrosis

SLC6A14 encodes an X-linked amino acid transporter expressed at the apical membrane of epithelial cells, colocated with CFTR in airway and intestinal epithelia. Variants in this gene have been investigated as modifiers of cystic fibrosis (CF) severity rather than primary causes of CF.

A genome-wide association study in 3,763 CF patients with meconium ileus identified five SNPs near SLC6A14 (minimum P = 1.28 × 10⁻¹² at rs3788766) accounting for ~5% of phenotypic variability, with replication in an independent cohort of 2,372 cases (P = 0.001) (PMID:22466613).

A meta-analysis of 6,365 CF patients demonstrated a significant locus on chrXq22-q23 encompassing AGTR2/SLC6A14 associated with lung disease severity (P = 1.8 × 10⁻⁹) (PMID:26417704). This effect was independent of classical CFTR genotypes.

Investigation of prenatal exocrine pancreatic damage by newborn immunoreactive trypsinogen (IRT) in 228 CF subjects found no significant association with SLC6A14 SNPs (P > 0.05) (PMID:25771386), indicating locus- and phenotype-specific effects.

In a cohort of 164 CF patients, multifactor dimensionality reduction revealed statistical interactions between rs3788766 in SLC6A14, other SLC family variants, and CFTR mutations impacting pancreatic insufficiency and digestive symptom onset (P = 0.015–0.036) (PMID:29635781).

Genetic evidence is limited to common variant associations without segregation in families or identification of rare pathogenic alleles. Functional assays specifically interrogating SLC6A14 activity in CF epithelia are lacking, and no animal or cellular rescue models have been reported.

Overall, SLC6A14 meets a Limited level of clinical validity as a CF modifier gene. While associations with meconium ileus and lung disease are established, absence of rare variant or segregation data and minimal functional validation preclude stronger classification. Further mechanistic studies are needed to elucidate its role and therapeutic potential.

Key Take-home: SLC6A14 variants are moderate risk modifiers of cystic fibrosis complications but currently lack sufficient evidence for clinical genetic testing beyond research contexts.

References

• Nature Genetics • 2012 • Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis. PMID:22466613
• The Journal of Pediatrics • 2015 • Variants in Solute Carrier SLC26A9 Modify Prenatal Exocrine Pancreatic Damage in Cystic Fibrosis. PMID:25771386
• 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

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