Association of TRPV5, CASR, and CALCR genetic variants with kidney stone disease susceptibility in Egyptians through main effects and gene–gene interactions

Abstract

Kidney stone disease (KSD) represents an urgent medical problem because of increasing its prevalence. Several functional polymorphisms in genes involved in the renal handling of calcium were associated with KSD pathogenesis. Among those, the rs4236480 of transient receptor potential vanilloid member 5 (TRPV5) gene, the rs1801725 of calcium-sensing receptor (CASR) gene, and the rs1801197 of calcitonin receptor (CALCR) gene appear to be of great importance. Due to the scarce data on the Egyptians, this study aimed to evaluate the association of these candidate genetic variants with the risk of developing KSD in an Egyptian population. To do so, the biochemical parameters were measured along with the genotyping of the three polymorphisms using allelic discrimination assay in 134 KSD patients and 86 age and sex-matched healthy subjects. The results showed that the genotypic distributions and allelic frequencies of the studied variants were significantly different between cases and controls. The three polymorphisms increased the risk of KSD significantly under all the tested genetic models (OR ranges from 2.152 to 5.994), except for the recessive model of the CALCR rs1801197 polymorphism after Bonferroni correction. The gene–gene interaction analyzed by multifactor dimensionality reduction selected the three-locus combination as the best model associated with the susceptibility to KSD with OR 9.706. Further, synergistic interactions were identified between TRPV5 rs4236480 and CALCR rs1801197 variants and CASR rs1801725 and CALCR rs1801197 variants. In conclusion, the TRPV5 rs4236480, CASR rs1801725, and CALCR rs1801197 polymorphisms showed a significant association with the risk of KSD in the Egyptian population. Furthermore, their complex interactions might have an impact on the genetic susceptibility to develop KSD.

Targeting TRP channels: recent advances in structure, ligand binding, and molecular mechanisms

“…Thoroughly reviewed in Dai et al (2010), Nishimura et al (2012), and Nilius and Voets (2013) TRPV5 Kidney stone (LOF) Khaleel et al, 2015;Oddsson et al, 2015;Wang et al, 2017;Ali et al, 2022 TRPV6 Chronic pancreatitis (LOF) Masamune et al, 2020;Zou et al, 2020 Transient neonatal hyperparathyroidism (LOF) Burren et al, 2018;Suzuki et al, 2018Suzuki et al, , 2020Yamashita et al, 2019;Almidani et al, 2020;Mason et al, 2020 Kidney stone (GOF) Inherited cardiac conduction defects, including progressive familial heart block type 1 (GOF), childhood atrioventricular block Kruse et al, 2009;Liu et al, 2010;Daumy et al, 2016;Syam et al, 2016;Xian et al, 2018;Janin et al, 2019;also Bassi et al, 2000;Sun et al, 2000 TRPML3 Varitint-waddler (Va) deafness (GOF) (in mice) Xu et al, 2007;Cuajungco and Samie, 2008;Nagata et al, 2008 TRPP2 Autosomal dominant polycystic kidney disease (LOF) Mochizuki et al, 1996;Wu and Somlo, 2000 GOF, gain of function; LOF, loss of function.…”

CALCR exacerbates renal cell carcinoma progression via stabilizing CD44

“…Studies have reported that CALCR plays a crucial role in maintaining quiescence in muscle stem cells [ 10 ]. CALCR gene polymorphisms is involved in calcium urolithiasis in Russian population [ 11 ] and kidney stone disease in Egyptians [ 12 ]. Additionally, CALCR expression in the medial amygdala is associated with social contact of females [ 13 ].…”