Association of Heterozygous CLDN10 Protein-Truncating Variants with CKD, Proteinuria, and Gout: Insights from the Geisinger MyCode/DiscovEHR Study

Background: The CLDN10 gene encoding the tight junction protein Claudin-10, is crucial for paracellular ion transport in the kidney's thick ascending limb. Previous studies have implicated CLDN10 in a Hypokalemic-Alkalotic Salt-Losing Tubulopathy, an autosomal recessive tight junction disease, characterized by reduced renal calcium and magnesium excretion. Heterozygous protein truncating variants (PTVs) in CLDN10 have been associated with increased markers of renal function, such as cystatin C, urea, urate, and creatinine. We analyzed data from the Geisinger MyCode/DiscovEHR study to expand our understanding of the renal phenotypes in individuals heterozygous for PTV’s in CLDN10. Methods: We identified individuals heterozygous for CLDN10 PTVs using data from Geisinger MyCode/DiscovEHR, an unselected health system-based cohort (n=174172) in central and northeast Pennsylvania with available exome sequencing and electronic health record data. We used linear regression, adjusted for age, sex, and genetic ancestry, to determine whether CLDN10 PTV heterozygosity was associated with lower estimated glomerular filtration rate (eGFR). Using Firth logistic regression, we also estimated risk for dipstick proteinuria, gout, hypokalemia, and hypocalcemia. Electronic medical records were examined to provide additional context on phenotypic features of CLDN10 heterozygotes. Results: Among 42 individuals who were heterozygous for CLDN10 PTVs (mean age: 53.5 ± 6.3 years; 16 males, 26 females), 19 had hypertension, 14 had diabetes mellitus, 10 had chronic kidney disease, 15 had 1+ or greater persistent proteinuria, 4 had gout, 3 had nephrolithiasis, 1 patient had end-stage kidney disease at age 70 years attributed to diabetes; no patients had overt hypokalemia, hypercalcemia or hypermagnesemia. Compared to non-carriers, CLDN10 PTV heterozygotes had lower eGFR (-14.8, 95% CI: -26.13, -3.55; p=0.01), and were at higher risk of eGFR<60 (OR 4.16, 95% CI: 1.91, 9.04; p<0.001), 1+ persistent proteinuria (OR 2.83, 95% CI: 1.47-5.46, p=0.002, and 2+ persistent proteinuria (OR 3.13, 95% CI: 1.49, 6.60; p=0.003), and gout (OR 8.37, 95% CI: 1.81, 38.72; p=0.007). Conclusion: CLDN10 PTV heterozygotes are at increased risk of CKD as well as mild to moderate proteinuria and gout. Funding: Private Foundation Support