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Abstract: FR-PO523

Common CLDN2 Variants Are Associated with Kidney Stone Risk and Reduced Claudin-2 Expression in Human Tissue

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic


  • Curry, Joshua N., University of Kansas School of Medicine, Kansas City, Kansas, United States
  • Tanikawa, Chizu, The University of Tokyo, Minato-ku, Tokyo, Japan
  • Kamatani, Yoichiro, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
  • Matsuda, Koichi, The University of Tokyo, Minato-ku, Tokyo, Japan
  • Yu, Alan S.L., University of Kansas Medical Center, Kansas City, Kansas, United States

The majority of calcium reabsorption in the proximal tubule (PT) occurs by an unknown route, although many studies suggest it is a passive process. The claudin family of proteins are tight junction proteins that in part modulate paracellular permeability and passive reabsorption in the kidney. The isoform claudin-2 forms cation-selective pores in vitro and is highly expressed in the PT. We previously showed that Cldn2-/y mice exhibit hypercalciuria and nephrocalcinosis, both of which are major risk factors for the development of kidney stones. We hypothesized that CLDN2 polymorphisms would associate with susceptibility for nephrolithiasis. To date, genome-wide association studies of nephrolithiasis have excluded CLDN2 from their analyses due to its location on the X chromosome.


Twelve SNPs in the CLDN2 locus passed our inclusion criteria and were assessed by logistic methods for disease association in two separate patient populations. Meta-analysis of the 2 studies was subsequently conducted using METAL with a total of 11,130 kidney stone cases and 187,639 controls. Using the dataset from the Genotype-Tissue Expression (GTEx) project, we analyzed cis-acting eQTLs in the CLDN2 locus. GTEx has insufficient kidney samples for eQTL analysis, but human kidney cortex and pancreas both exclusively express the same transcript (ENST00000540876.1). Thus, we analyzed pancreatic claudin-2 expression in association with CLDN2 risk variants.


Our findings show that 9 CLDN2 SNPs were associated with nephrolithiasis with p-values of 0.0462-0.0055. Given our findings in Cldn2-/y mice, we predicted that CLDN2 risk variants for kidney stones would lead to reduced claudin-2 expression. In 6 of the 7 CLDN2 SNPs available for eQTL analysis using GTEx, nephrolithiasis risk alleles were strongly associated with decreased pancreatic claudin-2 expression.


Our present findings suggest that common CLDN2 variants lead to reduced claudin-2 expression and thereby increase the risk for human kidney stone formation.


  • NIDDK Support