Study of the Association betweenITPKCGenetic Polymorphisms and Calcium Nephrolithiasis

Abstract

Nephrolithiasis is a multifactorial disease caused by environmental, hormonal, and genetic factors. Genetic polymorphisms of ORAI1, which codes for the main subunit of the store-operated calcium (SOC) channel, were reported to be associated with the risk and recurrence of calcium nephrolithiasis. Inositol 1,4,5-trisphosphate (IP3) 3-kinase C (ITPKC) is a negative regulator of the SOC channel-mediated signaling pathway. We investigated the association between calcium containing nephrolithiasis and genetic variants of ITPKC gene in Taiwanese patients. 365 patients were recruited in this study. Eight tagging single nucleotide polymorphisms of ITPKC were selected for genotyping. ITPKC genotypes were determined by TaqMan assay. ITPKC plasmids were transfected into cells to evaluate the intracellular calcium mobilization. Our results indicated that rs2607420 CC genotype in the intron region of the ITPKC gene is associated with a lower eGFR by both Modification of Diet in Renal Diseases (P = 0.0405) and Cockcroft-Gault (P = 0.0215) equations in patients with calcium nephrolithiasis. Our results identify a novel polymorphism for renal function and highlight the importance of ITPKC as a key molecule to regulate calcium signaling.

A Single Nucleotide Polymorphism (rs4236480) in TRPV5 Calcium Channel Gene Is Associated with Stone Multiplicity in Calcium Nephrolithiasis Patients

“…A family history of nephrolithiasis increases an individual's predisposition for a higher risk of kidney-stone formation [ 35 , 36 ], which substantially implies a susceptibility to genetic causes. Polymorphisms in multiple genes have been recently reported to be associated with the renal stone formation, that include calcium-sensing receptor ( CASR ), vitamin D receptor ( VDR ), and osteopontin ( OPN ), inositol 1,4,5-trisphosphate (IP3) 3-kinase C ( ITPKC ), and ORAI1 and claudin 14 ( CLDN14 ) genes [ 15 , 26 , 37 ].…”

“…Blood cells were first treated with 0.5% sodium dodecylsulfate lysis buffer and then with protease K (1 mg/mL) for 4 h at 60°C to digest nuclear proteins. A Gentra (QIAGEN, Valencia, CA) extraction kit and 70% alcohol precipitation were used for DNA extraction by a method described in the previous study [ 26 ].…”

“…After the PCR, the fluorescence was measured and analyzed using system SDS software version 1.2.3 (Applied Biosystems). We followed the protocol which was previously reported [ 26 ].…”

Genetic polymorphisms as prognostic factors for recurrent kidney stones: A systematic review and meta-analysis

“…In addition, several polymorphisms associated with kidney stone recurrence were only evaluated in a single study, such as in the androgen receptor (AR) gene [cytosine, adenine, guanine (CAG) repeat] [31], calcitonin receptor (CALCR) gene [AluI, IVS1-6T>C, IVS1insA, IVS5-17 (GTTT)3, IVS6A>G, IVS6G>A, IVS10+35-37delT, Ex13T>C, Ex13A>C, and 3 0 UTR+-18C>T] [32,33], calcium-sensing receptor (CASR) gene (A986S, E1011Q, R990G, rs1048213, rs1501899, rs17251221, rs6776158, rs7648041, rs7648044, rs7652589, and rs7627468) [34][35][36][37], e-cadherin (CDH1) gene (PmlI) [38], cytochrome P450c17α enzyme (CYP17) gene (MspAI) [39], epidermal growth factor receptor (EGFR) gene (BsrI) [39], estrogen receptor (ER) gene [thymine-adenine (TA) dinucleotide repeat] [31], insulin-like growth factor-2 (IGF2) gene (ApaI) [39], interleukin-18 (IL18) gene (-607C/A, -137G/C, and +105A/C) [40], IL-1 receptor antagonist (IL1RA) gene (intron 2 variable number of tandem repeats) [41], IL1B gene (promoter, exon 5, and rs16944) [41,42], IL6 gene (rs1800795, rs1800796, and rs1800797) [42], inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene (rs11673492, rs28493229, rs7257602, rs7251246, rs890934, rs10420685, rs2607420, and rs2290692) [43], manganese superoxide dismutase (Mn-SOD) gene (BsaWI) [44], melatonin receptor 1A (MTNR1A) gene (rs2119882, rs2375801, rs13140012, and rs6553010) [45], osteopontin (OPN) gene [9402 (Arg/His) and rs1126616] [46,47], Ca release-activated calcium channel protein 1 (ORAI1) gene (rs12313273) [48], ornithine decarboxylase (ODC) gene (+316 G/A) [49], osteocalcin gene (HindIII) [50], renal sodium-citrate (dicarboxylate) cotransporter (hNaDC1; SLC13A2) gene (I550V [51], rs11567842 [29]), regulator of G protein signaling 14 (RGS14) gene (rs12654812) [34], spermidine/spermine N1-acetyltransferase 1 (SAT1) gene (−1415 T/C) [49], transporter associated with antigen-processing (TAP) gene (DpnII, AccI, BstUI, MspI, and RsaI)…”

The rs1256328 (ALPL) and rs12654812 (RGS14) Polymorphisms are Associated with Susceptibility to Calcium Nephrolithiasis in a Taiwanese population

“…The TRPV5 and CLCN5 genes were also proven to be important in the pathogenesis of nephrolithiasis 18,19 . In addition, genetic polymorphisms of calcium channel, ORAI1 (rs12313273, rs7135617, and rs6486795), were reporetd to associate with the development of nephrolithiasis 20 ITPKC (rs2607420) is also associated with the estimated creatinine clearance in nephrolithiasis patients 21 .…”