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Primary Hyperparathyroidism and the Presence of Kidney Stones Are Associated with Different Haplotypes of the Calcium-Sensing Receptor

Units of Endocrinology (A.S., C.B., M.L.M., S.Mu.) and Genetics (V.G., L.A.M., L.D.), Hospital "Casa Sollievo della Sofferenza," Instituto di Ricovero e Cura a Carattere Scientifico, San Giovanni Rotondo (Foggia), Italy; Department of Clinical Science (S.D.G., S.Mi., M.L.M.), University of Roma, Rome, Italy; "San Giuseppe Fatebenefratelli" Hospital (I.C.), Associazione Fatebenefratelli per la Ricerca, Milan, Italy; Department of Endocrinology (M.C.), University of Foggia, Foggia, Italy; Department of Internal Medicine (F.B.), University of Verona, Verona, Italy; Department of Endocrinology (C.M.F.), University of Ancona, Ancona, Italy; Department of Internal Medicine (N.M.), University of Bologna, Bologna, Italy; Department of Endocrinology (A.P.), University of Torino, Torino, Italy; Departments of Medicine, Physiology, and Human Genetics (G.N.H.), McGill University, Montreal, Quebec, Canada H3A 1A1; and Departments of Laboratory Medicine and Pathobiology (D.E.C.C.), Medicine, and Genetics, University of Toronto, Toronto, Ontario, Canada M5G 115

Address all correspondence and requests for reprints to: Alfredo Scillitani, Unit of Endocrinology, "Casa Sollievo della Sofferenza" Hospital, IRCCS, 71013 San Giovanni Rotondo (FG), Italy. E-mail: alscill{at}tin.it.

Introduction: 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).

Patients and 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.

Conclusion: 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.

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