CASR, CLDN 14, ALPL & SLC34A1 genes are associated with the risk of nephrolithiasis in Egyptian children

Backgrounds: The pathophysiology of nephrolithiasis is complex, influenced by both environmental and genetic factors. Calcium is the most prevalent metabolite present in the stone matrix. Stimulating the basolateral calcium sensing receptor (CASR) in the renal tubules leads to an increase in claudin-14 expression, reducing paracellular calcium permeability and increasing urinary Ca²⁺ excretion. Alkaline phosphatase (ALPL) hydrolyzes the pyrophosphate to free phosphate, proposing its potential role in nephrolithiasis development. Solute carrier family 34 member 1 (SLC34A1) encodes Na+-Pi cotransporter 2a, playing a key role in renal absorption of phosphate. We aimed to detect the risk of CASR, CLDN14, ALPL, and SLC34A1 gene polymorphisms on the development of nephrolithiasis in the Egyptian children.

Methods: We enrolled 143 children diagnosed with nephrolithiasis and 112 healthy controls. Real-time polymerase chain reaction analysis of CASR (rs1801725 G/T & rs73186030 C/T), CLDN14 (rs219780 C/T & rs199565725 AC/del), ALPL (rs149344982 A/G, rs1976403 A/C & rs1256328 C/T), and SLC34A1 (rs11746443 G/A) single-nucleotide polymorphisms (SNPs) were performed.

Results: We observed that children carrying the T allele of CASR rs1801725, CLDN14 rs219780, and ALPL rs1256328 SNPs were at a greater risk of nephrolithiasis compared to the control group (p = 0.003, p < 0.001, and p = 0.001, respectively). The children with the del allele of CLDN14 rs199565725 and the ALPL rs1976403 C allele had a significantly higher risk of developing nephrolithiasis compared to the control group (p = 0.007 & p = 0.001, respectively). The individuals who have the A allele of ALPL rs149344982 and SLC34A1 rs11746443 had a significantly higher risk of nephrolithiasis compared to the control group (p < 0.001). We found that CLDN14 rs219780 CT, ALPL rs149344982 AG, ALPL rs1256328 TT, and SLC34A1 rs11746443 GA genotypes were the final predictors of nephrolithiasis in children (p < 0.05). Individuals with ATAT and GTAT haplotypes had approximately a 29- and 19-fold increased risk of nephrolithiasis.

Discussion: Nephrolithiasis is a complex disease caused by genetic and environmental factors. It would be beneficial if, among patients with recurrent kidney stones, the nephrologists could identify patients at high risk who would benefit from personalized therapy, a controlled lifestyle, and regular check-ups using the necessary investigation. There are several gene polymorphisms that were identified as the risk factor for developing nephrolithiasis. We found that CASR rs1801725 G/T, CLDN14 rs199565725 AC/del & rs219780 C/T, ALPL rs149344982 A/G, rs1976403 A/C & rs1256328 C/T, SLC34A1 rs11746443 G/A were associated with an increased risk of nephrolithiasis in Egyptian children. The study limitations include a lack of detailed information on nephrolithiasis risk factors such as diet and body mass index.

Conclusion: CLDN14 rs219780 CT, ALPL rs149344982 AG, ALPL rs1256328 TT, and SLC34A1 rs11746443 GA genotypes were the final predictors of nephrolithiasis in children.