Primary hyperparathyroidism and the presence of kidney stones are associated with different haplotypes of the calcium-sensing receptor.
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.
Scillitani
Alfredo
A
Units of Endocrinology, Hospital Casa Sollievo della Sofferenza, Instituto di Ricovero e Cura a Carattere Scientifico, San Giovanni Rotondo (Foggia), Italy. alscill@tin.it
Guarnieri
Vito
V
Battista
Claudia
C
De Geronimo
Simona
S
Muscarella
Lucia Anna
LA
Chiodini
Iacopo
I
Cignarelli
Mauro
M
Minisola
Salvatore
S
Bertoldo
Francesco
F
Francucci
Cristiano M
CM
Malavolta
Nazzarena
N
Piovesan
Alessandro
A
Mascia
Maria Lucia
ML
Muscarella
Silvana
S
Hendy
Geoffrey N
GN
D'Agruma
Leonardo
L
Cole
David E C
DE
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
D044169:Receptors, Calcium-Sensing