Annalisa Terranegra

Influence of Calcium-Sensing Receptor Gene on Urinary Calcium Excretion in Stone-Forming Patients

Calcium-sensing receptor (CaSR) is a plasma membrane protein that regulates tubular reabsorption of Ca. To establish its role in idiopathic hypercalciuria, the association of urinary Ca excretion with the polymorphisms of CASR gene has been studied in healthy subjects and in hypercalciuric and normocalciuric Ca stone formers. CASR exon 7 single nucleotide polymorphisms (SNP), G/T at codon 986, G/A at codon 990, and C/G at codon 1011, were evaluated by PCR amplification and direct sequencing in 97 normocalciuric stone formers, 134 hypercalciuric stone formers, and 101 normocalciuric healthy controls. Four haplotypes were defined on the basis of CASR gene SNP: haplotype 1 was characterized by the most frequent sequence; haplotypes 2, 3, or 4 by the presence of a single polymorphic variant at codon 986, 990, or 1011, respectively. The relative risk of hypercalciuria was calculated with multinomial logistic regression and was significantly increased only in individuals carrying haplotype 3 (Odds ratio, 13.0 [95% confidence interval, 1.7 to 99.4]). Accordingly, Ca excretion was higher in subjects bearing haplotype 3, whereas those bearing haplotype 2 showed a slight increase of plasma Ca concentration. Multiple regression analysis showed that haplotype 3 explained 4.1% of the total variance of Ca excretion and 12.6% of the variance explained by the variables considered in the study. In conclusion, CASR gene could be a component of the complex genetic background regulating Ca excretion. Arg990Gly polymorphism could facilitate activation of CaSR and increase Ca excretion and susceptibility to idiopathic hypercalciuria.

Decreased transcriptional activity of calcium-sensing receptor gene promoter 1 is associated with calcium nephrolithiasis

BACKGROUNDnCaSR gene is a candidate for calcium nephrolithiasis. Single-nucleotide polymorphisms (SNPs) encompassing its regulatory region were associated with calcium nephrolithiasis.nnnAIMSnWe tested SNPs in the CaSR gene regulatory region associated with calcium nephrolithiasis and their effects in kidney.nnnSUBJECTS AND METHODSnOne hundred sixty-seven idiopathic calcium stone formers and 214 healthy controls were genotyped for four CaSR gene SNPs identified by bioinformatics analysis as modifying transcription factor binding sites. Strontium excretion after an oral load was tested in 55 stone formers. Transcriptional activity induced by variant alleles at CaSR gene promoters was compared by luciferase reporter gene assay in HEK-293 and HKC-8 cells. CaSR and claudin-14 mRNA levels were measured by real-time PCR in 107 normal kidney medulla samples and compared in patients with different CaSR genotype.nnnRESULTSnOnly rs6776158 (A>G), located in the promoter 1, was associated with nephrolithiasis. Its minor G allele was more frequent in stone formers than controls (37.8% vs 26.4%, P = .001). A reduced strontium excretion was observed in GG homozygous stone formers. Luciferase fluorescent activity was lower in cells transfected with the promoter 1 including G allele at rs6776158 than cells transfected with the A allele. CaSR mRNA levels were lower in kidney medulla samples from homozygous carriers for the G allele at rs6776158 than carriers for the A allele. Claudin-14 mRNA levels were also lower in GG homozygous subjects.nnnCONCLUSIONSnMinor allele at rs6776158 may predispose to calcium stones by decreasing transcriptional activity of the CaSR gene promoter 1 and CaSR expression in kidney tubules.

Calcium-sensing receptor gene polymorphisms in patients with calcium nephrolithiasis.

Purpose of reviewThe calcium-sensing receptor gene (CaSR, chr. 3q13.3–21) is a candidate to explain nephrolithiasis. This review analyzes the potential role of CaSR in lithogenesis according to findings of functional and genetic studies. Recent findingsCaSR is a cation receptor located in the tubular cell plasma membrane. Its activation decreases calcium reabsorption in the ascending limb and distal convoluted tubule, but increases phosphate reabsorption in proximal tubules and decreases water and proton reabsorption in collecting ducts. Its effects in proximal tubules and collecting ducts can limit the calcium phosphate precipitation risk induced by the increase in calcium excretion. The nonconservative CaSR gene Arg990Gly polymorphism was associated with nephrolithiasis and hypercalciuria in different populations. Arg990Gly is located on exon 7 and produces a gain of the CaSR function. rs7652589 and rs1501899 were also associated with nephrolithiasis in patients with normal citrate excretion. These polymorphisms are located in the CaSR gene regulatory region and may modify CaSR gene promoter activity. SummaryThe activating Arg990Gly polymorphism may predispose to nephrolithiasis by increasing calcium excretion. Polymorphisms at the regulatory region may predispose to nephrolithiasis by changing tubular expression of the CaSR. CaSR genotype may be a marker to identify patients prone to develop calcium nephrolithiasis.

Potential Nutrigenomic Approaches to Reduce the High Incidence of Obesity in Qatar

Obesity prevalence has been growing exponentially over the last few decades, with a high impact in high-income countries, like Qatar. Several approaches are attempting to understand the causes of this phenomenon however more important is what to do to reverse the trends. Obesity is widely studied, mostly in Europe and the Unites States, and a number of studies have demonstrate the role of specific gene patterns, transcriptome and proteome pathways, and gut microbiome strains. The Omics sciences have a great potential to investigate the determinants of non-communicable diseases, such as obesity. Nutritional genomics sciences apply all the Omics approaches to address nutrition-related diseases, investigating the interaction between genes and diet. To date, few data are available from nutrigenomic studies conducted in Middle East and particularly in Qatar to help the design of targeted interventions. The high incidence of obesity and the peculiar genetic make-up of the Qatari population provide opportunities for exploring nutrigenomic approaches to help addressing the problem.

Nephrolithiasis and nutrition in obesity

Background Obesity is a risk factor for nephrolithiasis (NL). According to an American study of a large cohort with a BMI >30, males increased the risk of NL of 30% and females of 200%. Moreover, diet plays an important role as NL risk factor, mainly in those western countries characterized by a large meet consume. This epidemiology study investigated the NL frequency in an obese Italian population, also considering the relation with metabolic syndrome and interaction with diet.