title: Primary hyperparathyroidism and the presence of kidney stones are associated with different haplotypes of the calcium-sensing receptor.
abstract: BACKGROUND
  Three single-nucleotide polymorphisms in the calcium-sensing receptor gene (CASR) encoding the missense substitutions A986S, R990G, and Q1011E have been associated with normal variation in extracellular calcium homeostasis, both individually and in haplotype combination. The aim of this study was to examine haplotype associations in primary hyperparathyroidism (PHPT).
  
  
  METHODS
  Patients with sporadic PHPT (n = 237) were recruited from endocrine clinics and healthy controls (n = 433) from a blood donor clinic, and levels of serum calcium, albumin, and PTH were measured. In PHPT patients, urinary calcium/creatinine clearances and bone mineral density at spine and femoral neck were measured and the presence of kidney stones and vertebral fractures identified. The CASR single-nucleotide polymorphisms were haplotyped by allele-specific sequencing.
  
  
  RESULTS
  Four haplotypes (ARQ, SRQ, AGQ, and ARE) of eight were observed, in keeping with significant linkage disequilibrium, but haplotype frequencies did not show significant Hardy-Weinberg disequilibrium. The SRQ haplotype was more common in PHPT (125 of 474 alleles) than in controls (170 of 866 alleles, P = 0.006) and showed a significant (P = 0.006) gene-dosage effect. There was no significant association between haplotype and bone mineral density or fractures, but association with kidney stones was significant (P = 0.0007). In the stone-forming subgroup, the SRQ haplotype was underrepresented and AGQ overrepresented. Patients bearing the AGQ haplotype had an odds ratio of 3.8 (95% confidence interval, 1.30-11.3) for presentation with renal stones compared with the rest.
  
  
  CONCLUSIONS
  Our data indicate that the CASR SRQ haplotype is significantly associated with PHPT in our population. Within the PHPT patient population, the AGQ haplotype is significantly associated with kidney stones.
authors.affiliation: Units of Endocrinology, Hospital Casa Sollievo della Sofferenza, Instituto di Ricovero e Cura a Carattere Scientifico, San Giovanni Rotondo (Foggia), Italy. alscill@tin.it
authors.forename: Alfredo
authors.initials: A
authors.lastname: Scillitani
authors.forename: Vito
authors.initials: V
authors.lastname: Guarnieri
authors.forename: Claudia
authors.initials: C
authors.lastname: Battista
authors.forename: Simona
authors.initials: S
authors.lastname: De Geronimo
authors.forename: Lucia Anna
authors.initials: LA
authors.lastname: Muscarella
authors.forename: Iacopo
authors.initials: I
authors.lastname: Chiodini
authors.forename: Mauro
authors.initials: M
authors.lastname: Cignarelli
authors.forename: Salvatore
authors.initials: S
authors.lastname: Minisola
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertoldo
authors.forename: Cristiano M
authors.initials: CM
authors.lastname: Francucci
authors.forename: Nazzarena
authors.initials: N
authors.lastname: Malavolta
authors.forename: Alessandro
authors.initials: A
authors.lastname: Piovesan
authors.forename: Maria Lucia
authors.initials: ML
authors.lastname: Mascia
authors.forename: Silvana
authors.initials: S
authors.lastname: Muscarella
authors.forename: Geoffrey N
authors.initials: GN
authors.lastname: Hendy
authors.forename: Leonardo
authors.initials: L
authors.lastname: D'Agruma
authors.forename: David E C
authors.initials: DE
authors.lastname: Cole
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D006239:Haplotypes; D006801:Humans; D049950:Hyperparathyroidism, Primary / Q000235:genetics*; D007669:Kidney Calculi / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D044169:Receptors, Calcium-Sensing / Q000235:genetics*; D012044:Regression Analysis
chemical_list: D044169:Receptors, Calcium-Sensing