BES2003 Poster Presentations Bone (13 abstracts)
Functional and association studies of calcium sensing receptor polymorphisms and mediators of calcium homeostasis
B Harding 1 , AJ Curley 1 , PT Christie 1 , MR Bowl 1 , JJO Turner 1 , M Barber 2 , G Hampson 3 , T Spector 2 & RV Thakker 1
1Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; 2Twin Research and Genetic Epidemiology Unit, The Guy's, King's College and St Thomas' Hospitals Medical and Dental School, University of London, London, UK; 3Department of Chemical Pathology, The Guy's, King's College and St Thomas' Hospitals Medical and Dental School, University of London, London, UK.
The calcium sensing receptor (CaSR) plays a central role in altering the secretion of parathyroid hormone (PTH) in response to alterations in extracellular calcium, and four studies have reported an association between CaSR polymorphisms and serum Ca 2+, serum PTH, and bone mineral density (BMD). However, two other studies have failed to detect such associations. We have therefore undertaken studies to investigate the Ala986Ser, Arg990Gly, and Gln1011Glu CaSR polymorphisms for associations between serum Ca 2+, serum PTH, serum 1,25(OH)2 vitamin D3, urinary calcium excretion and BMD in 110 adult, Northern European female, dizygotic twin pairs. Tests of association were carried out using STATA with the regress and cluster options . Functional evaluation of the CaSR polymorphisms was undertaken by transient expression in HEK293 cells and assessing their responses, as measured by changes in intracellular calcium concentration to alterations in extracellular calcium. Our results found a lack of association between each of these CaSR polymorphisms and each of the following: serum Ca 2+; serum Ca 2+ corrected for serum albumin; serum Ca 2+ corrected for age; serum PTH; serum 1,25(OH)2 vitamin D3; 24 hour urinary calcium excretion; urinary calcium and creatinine ratios; and BMD. These findings were also supported by detecting an absence of functional differences in the dose-response curves of the CaSR variants with the EC50 values (mean plus/minus SD) of the Wild Type (Ala986/Arg990/Gln1011), Ser986, Gly990 and Glu1011 CaSR variants being 2.74plus/minus 0.29mM, 3.09 plus/minus 0.34mM, 2.99 plus/minus 0.23mM, and 2.96 plus/minus 0.30mM (p>0.4), respectively. Thus, these results indicate that:1) the CaSR polymorphisms of codons 986, 990 and 1011 do not lead to altered set-points of the CaSR and 2) that these CaSR polymorphisms do not have a significant influence on serum Ca 2+, PTH, and 1,25(OH)2 vitamin D3, urinary calcium excretion or bone mineral density.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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