Clinical kidney journal
July 16, 2026 · via Europe PMC
Novel associations of Claudin gene variants with kidney stone disease.
Liu IY, Haverfield J, MacKenzie E, Dufresne L, Ryan AK, Engert JC, Gupta IR.
AI summary — for doctors, generated from the abstract only
Claudin family variants beyond known FHHNC genes were associated with kidney stone risk in UK Biobank.
What was studied
Genetic association study of 415,237 UK Biobank participants (9,009 stone cases) across all 24 CLDN genes.
Key findings
- 43 novel coding variant associations were found, including CLDN16 variants with large effect sizes (OR 42.2 and 60.5).
- CLDN19 p.Arg200Gln replicated (OR 1.23) and related to lower phosphate.
- 13 novel loci were found near CLDN2, CLDN10, CLDN11, CLDN18 and others.
Clinical relevance
Expands stone genetics and may identify patients for genetic evaluation.
Who should care
Limitations
Rare variant ORs have wide uncertainty and need functional and clinical validation.
Consider genetic evaluation in early or recurrent stone formers with hypomagnesemia or hypercalciuria.
This is an AI-generated summary of the published abstract, not a clinical recommendation. It may not reflect the full text or subsequent updates — verify against the original source before acting on it.
Abstract
Background
The tight junction family of claudin proteins regulates paracellular ion transport in the nephron and across epithelial and endothelial barriers throughout the body. Rare recessive variants in CLDN16 and CLDN19 cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), while common variants in CLDN2, CLDN10, and CLDN14 have been associated with kidney stones. Despite evidence that most claudin proteins are expressed within the nephron, their genetic contribution to kidney stone susceptibility has not been systematically explored.
Methods
We analyzed 415 237 UK Biobank participants (9009 kidney stone cases and 406 228 controls) using exome sequencing and imputed genotype data spanning all 24 human CLDN genes. Single-variant association testing, gene burden analysis, and phenome-wide association studies were employed to identify novel associations.
Results
Forty-three novel coding variant associations were identified through exome sequencing, including two CLDN16 variants: p.Gly57Arg (rs747654138; odds ratio [OR] = 42.2, P = 9.5 × 10-8) and p.Arg146His (rs772241737; OR = 60.5, P = 8.1 × 10-4). We replicated a known association with a CLDN19 variant, p.Arg200Gln (rs116804195; OR = 1.23, P = 2.6 × 10-4), which was also associated with decreased serum phosphate and increased alkaline phosphatase. We also identified 13 novel susceptibility loci within the imputed genotype dataset, including single nucleotide polymorphisms near CLDN2, CLDN10, CLDN11, CLDN18, and CLDN22-CLDN24 (all P CLDN14 association.
Conclusions
Beyond established FHHNC genes, multiple CLDN family members harbor variants potentially influencing kidney stone risk, possibly through altered paracellular transport and mineral homeostasis. These findings expand kidney stone genetic architecture and suggest that claudin proteins merit further investigation in its pathogenesis.
DOI
10.1093/ckj/sfag237
PMID
42824688
PMCID
PMC13627830
Research metadata (titles, abstracts, authors, publication dates) is sourced from Europe PMC, which aggregates content from PubMed/MEDLINE, PubMed Central, and other providers under the U.S. National Library of Medicine (NLM/NCBI). NLM does not claim copyright on abstracts; the original journal publishers or authors may hold rights to the full articles. AI-generated summaries are derived only from the abstract, never the full text, and are always labeled as AI-generated.
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