Calcium kidney stones are associated with a haplotype of the calcium-sensing receptor gene regulatory region

Abstract

Three haplotype blocks were identified in the CaSR gene. The first block was characterized by six SNPs and included gene promoters. The rs7652589 and rs1501899 SNPs and the CATTCA haplotype of the first block were significantly more frequent in normocitraturic calcium kidney stone formers than controls. The risk of stones was increased in normocitraturic homozygous patients and heterozygotes for the CATTCA haplotype. The rate of stones was higher in stone formers with the CATTCA haplotype. In a three-generation family, calcium stones were associated with the CATTCA haplotype. The bioinformatic analysis identified a new site for the octamer-binding transcription factor 1 in the presence of the variant alleles at the rs7652589 and rs1501899 SNPs. This transcription factor may downregulate the transcription of vitamin D-dependent genes and the CaSR expression. Conclusion. SNPs and CATTCA haplotype of the CaSR gene first block is associated with kidney stones in normocitraturic patients.

Polymorphisms at the regulatory regions of the CASR gene influence stone risk in primary hyperparathyroidism

“…These SNPs have not been functionally characterized, but their location in the CASR gene regulatory region including the gene promoters suggested that they might influence CASR expression. The bioinformatic analysis with the prediction tool MATCH 11.2 and the TRANSFAC 12.1 database on eukaryotic transcriptional regulation indicated that the variant alleles at rs7652589 and rs1501899 SNPs resulted in changes in transcription factors binding sites that downregulate CASR expression (14). This suggestion was consistent with the higher plasma levels of PTH found in idiopathic stone formers carrying these variant alleles (14).…”

“…1). Genotyping was performed with the 5 0 nuclease assay technology for allelic discrimination using fluorigenic probes in a specific Taqman SNP genotyping assay (Applied Biosystems, Foster City, CA, USA) as previously described (14). Amplification was performed in 8 ml final volume with 20 ng genomic DNA at the following conditions: 95 8C for 20 s, and 40 cycles each at 95 8C for 3 s, and 60 8C for 30 s. SNP variation was assessed by means of the allelic discrimination assay employing the Applied Biosystems Software Package SDS 2.1.…”

“…The bioinformatic analysis with the prediction tool MATCH 11.2 and the TRANSFAC 12.1 database on eukaryotic transcriptional regulation indicated that the variant alleles at rs7652589 and rs1501899 SNPs resulted in changes in transcription factors binding sites that downregulate CASR expression (14). This suggestion was consistent with the higher plasma levels of PTH found in idiopathic stone formers carrying these variant alleles (14). To confirm these findings in PHPT, the present work explored the distribution of the alleles at the rs7652589 and rs1501899 SNPs and their association with kidney stones in PHPT patients.…”

The Search for Monogenic Causes of Kidney Stones

“…Previous studies have suggested that the activity of the CaSR is a determinant of urinary calcium excretion, and that SNPs in the encoding gene have hereditary influences. 15 Other studies have not confirmed these observations. However, the absence of mutations here does not rule out an effect of SNPs on the kidney stone phenotype.…”

Kidney stone disease: pathophysiology, investigation and medical treatment

“…Stones develop in hyperparathyroid patients with allelic variants that cause reduced expression of the CaSR, with associated loss of its urinary dilution and acidification effect. 15 …”