Novel associations of Claudin gene variants with kidney stone disease

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 CLDN proteins are expressed within the nephron, their genetic contribution to kidney stone susceptibility has not been systematically explored. Methods We analysed 415 237 UK Biobank participants (9 009 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 43 novel coding variant associations were identified through exome sequencing, including two CLDN16 variants: p.Gly57Arg (rs747654138; OR = 42.23, P = 9.54 × 10−8) and p.Arg146His (rs772241737; OR = 60.45, P = 8.12 × 10−4). We replicated a known association with a CLDN19 variant, p.Arg200Gln (rs116804195; OR = 1.23, P = 2.57 × 10−4), which was also associated with decreased serum phosphate and increased alkaline phosphatase. We also identified 12 novel susceptibility loci within the imputed genotype dataset, including single nucleotide polymorphisms near CLDN2, CLDN10, CLDN11, CLDN18, and CLDN22–CLDN24 (all P < 0.00015), and confirmed a known CLDN14 association. Conclusions Beyond established FHHNC genes, multiple CLDN family members harbour variants potentially influencing kidney stone risk, possibly through altered paracellular transport and mineral homeostasis. These findings expand kidney stone genetic architecture and suggest that CLDN proteins merit further investigation in its pathogenesis.