title: Polymorphisms at the regulatory regions of the CASR gene influence stone risk in primary hyperparathyroidism.
abstract: OBJECTIVE
  Single nucleotide polymorphisms (SNPs) of the calcium-sensing receptor (CASR) gene at the regulatory region were associated with idiopathic calcium nephrolithiasis. To confirm their association with nephrolithiasis, we tested patients with primary hyperparathyroidism (PHPT).
  
  
  METHODS
  A genotype-phenotype association study.
  
  
  METHODS
  In all, 332 PHPT patients and 453 healthy controls were genotyped for the rs7652589 (G>A) and rs1501899 (G>A) SNPs sited in the noncoding regulatory region of the CASR gene. Allele, haplotype, and diplotype distribution were compared between PHPT patients and controls, and in stone forming and stone-free PHPT patients.
  
  
  RESULTS
  The allele frequency at rs7652589 and rs1501899 SNPs was similar in PHPT patients and controls. The A minor alleles at these two SNPs were more frequent in stone forming (n=157) than in stone-free (n=175) PHPT patients (rs7652589: 36.9 vs 27.1%, P=0.007; rs1501899: 37.1 vs 26.4%, P=0.003). Accordingly, homozygous or heterozygous PHPT patients for the AA haplotype (n=174, AA/AA or AA/GG diplotype) had an increased stone risk (odds ratio 1.83, 95% confidence interval 1.2-2.9, P=0.008). Furthermore, these PHPT patients had higher serum concentrations of ionized calcium and parathyroid hormone (1.50 ± 0.015 mmol/l and 183 ± 12.2 pg/ml) than patients with the GG/GG diplotype (n=145, 1.47 ± 0.011 mmol/l (P=0.04) and 150 ± 11.4 pg/ml (P=0.049)). Using a logistic regression model, the increase in stone risk in PHPT patients was predicted by AA/AA or AA/GG diplotype, the highest tertile of serum ionized calcium values and the lowest tertile of age.
  
  
  CONCLUSIONS
  Polymorphisms located in the regulatory region of the CASR gene may increase susceptibility of the PHPT patients to kidney stone production.
authors.affiliation: Nephrology and Dialysis Unit, Postgraduate School of Nephrology, Vita Salute University, San Raffaele Scientific Institute, 20132 Milan, Italy. vezzoli.giuseppe@hsr.it
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Vezzoli
authors.forename: Alfredo
authors.initials: A
authors.lastname: Scillitani
authors.forename: Sabrina
authors.initials: S
authors.lastname: Corbetta
authors.forename: Annalisa
authors.initials: A
authors.lastname: Terranegra
authors.forename: Elena
authors.initials: E
authors.lastname: Dogliotti
authors.forename: Vito
authors.initials: V
authors.lastname: Guarnieri
authors.forename: Teresa
authors.initials: T
authors.lastname: Arcidiacono
authors.forename: Vera
authors.initials: V
authors.lastname: Paloschi
authors.forename: Francesco
authors.initials: F
authors.lastname: Rainone
authors.forename: Cristina
authors.initials: C
authors.lastname: Eller-Vainicher
authors.forename: Loris
authors.initials: L
authors.lastname: Borghi
authors.forename: Antonio
authors.initials: A
authors.lastname: Nouvenne
authors.forename: Angela
authors.initials: A
authors.lastname: Guerra
authors.forename: Tiziana
authors.initials: T
authors.lastname: Meschi
authors.forename: Franca
authors.initials: F
authors.lastname: Allegri
authors.forename: Daniele
authors.initials: D
authors.lastname: Cusi
authors.forename: Anna
authors.initials: A
authors.lastname: Spada
authors.forename: David E C
authors.initials: DE
authors.lastname: Cole
authors.forename: Geoffrey N
authors.initials: GN
authors.lastname: Hendy
authors.forename: Donatella
authors.initials: D
authors.lastname: Spotti
authors.forename: Laura
authors.initials: L
authors.lastname: Soldati
mesh_terms: D000328:Adult; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D049950:Hyperparathyroidism, Primary / Q000150:complications* / Q000235:genetics*; D007669:Kidney Calculi / Q000209:etiology* / Q000235:genetics*; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D053040:Nephrolithiasis / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D044169:Receptors, Calcium-Sensing / Q000235:genetics*; D012307:Risk Factors
chemical_list: D044169:Receptors, Calcium-Sensing