VITAMIN-D-RECEPTOR GENE POLYMORPHISM AND PARATHYROID CALCIUM SENSOR PROTEIN (CAS GP330) EXPRESSION IN PRIMARY HYPERPARATHYROIDISM/

Calcitriol, via its receptor (VDR), inhibits parathyroid hormone (PTH) secretion and cell proliferation. physically linked polymorphic MPI a lleles denoted b, a, and T, comprise a novel risk factor for postmenop ausal primary hyperparathyroidism (pHPT) by their presumed coupling to reduced VDR expression. This study examines VDR gene polymorphisms, p arathyroid calcium-regulated cytoplasmic calcium concentrations ([Ca2](i)) and parathyroid expression of a calcium sensor protein (CAS/gp33 0). Genomic DNA was obtained from 66 postmenopausal women with pHPT an d 66 age-matched female controls. Polymorphic MDR alleles were detecte d after polymerase chain reaction (PCR) and restriction digestion. Cry osections of pathologic parathyroid glands from 41 of the patients wer e immunostained with a monoclonal anti-CAS/gp330 antibody. Homozygosit y for the VDR alleles b, a, and T was overrepresented in pHPT (p < 0.0 1-0.05) but did not couple Po ED50 for calcium-regulated [Ca2+](i). Th e enlarged parathyroid glands possessed heterogeneous down-regulation of CAS/gp330, This down-regulation was the least conspicuous in the BE genotype and these few patients generally had larger parathyroid lesi ons (p < 0.05). The VDR haplotype baT is a risk factor for pHPT possib ly by hampering the regulatory actions of calcitriol. In contrast the BAt haplotype seems to be underrepresented in pHPT and to couple to la rger parathyroid lesions as web as less deranged CAS/gp330 expression and parathyroid cell function. HPT in these individuals may relate to genetic events principally altering the regulation of cell proliferati on, rather than calcium sensing of the parathyroid cells.