Functional characterization of calcium sensing receptor polymorphisms and absence of association with indices of calcium homeostasis and bone mineral density.
OBJECTIVE
Associations between calcium-sensing receptor (CaSR) polymorphisms and serum calcium, PTH and bone mineral density (BMD) have been reported by six studies. However, three other studies have failed to detect such associations. We therefore further investigated three CaSR coding region polymorphisms (Ala986Ser, Arg990Gly and Gln1011Glu) for associations with indices of calcium homeostasis and BMD and for alterations in receptor function.


METHODS
One hundred and ten adult, Caucasian, female, dizygotic twin pairs were investigated for associations between the three CaSR polymorphisms and serum calcium, albumin, PTH, 25-hydroxyvitamin D(3) (25OHD(3)), 1,25-dihydroxyvitamin D(3)[1,25(OH)(2)D(3)], urinary calcium excretion and BMD. Each polymorphic CaSR was also transfected into HEK293 cells and functionally evaluated.


RESULTS
There was a lack of association between each of these three CaSR polymorphisms and serum calcium corrected for albumin, PTH, 25OHD(3), 1,25(OH)(2)D(3), urinary calcium excretion or BMD at the hip, forearm and lumbar spine. These findings were supported by a lack of functional differences in the dose-response curves of the CaSR variants, with the EC(50) values (mean +/- SEM) of the wild-type (Ala986/Arg990/Gln1011), Ser986, Gly990 and Glu1011 CaSR variants being 2.74 +/- 0.29 mm, 3.09 +/- 0.34 mm (P > 0.4), 2.99 +/- 0.23 mm (P > 0.4) and 2.96 +/- 0.30 mm (P > 0.5), respectively.


CONCLUSIONS
Our study, which was sufficiently powered to detect effects that would explain up to 5%, but not less than 1%, of the variance has revealed that the three CaSR polymorphisms of the coding region have no major influence on indices of calcium homeostasis in this female population, and that they do not alter receptor function.
Harding
Brian
B
Academic Endocrine Unit, Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology, and Metabolism (OCDEM), University of Oxford, Churchill Hospital, Headington, Oxford, UK.
Curley
Alan J
AJ
Hannan
Fadil M
FM
Christie
Paul T
PT
Bowl
Michael R
MR
Turner
Jeremy J O
JJ
Barber
Mathew
M
Gillham-Nasenya
Irina
I
Hampson
Geeta
G
Spector
Tim D
TD
Thakker
Rajesh V
RV
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D015519:Bone Density / Q000502:physiology*; D002117:Calcitriol / Q000097:blood; D002118:Calcium / Q000097:blood / Q000378:metabolism* / Q000652:urine; D002460:Cell Line; D016000:Cluster Analysis; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006706:Homeostasis; D006801:Humans; D008875:Middle Aged; D010281:Parathyroid Hormone / Q000097:blood; D011110:Polymorphism, Genetic; D044169:Receptors, Calcium-Sensing / Q000235:genetics* / Q000378:metabolism; D012044:Regression Analysis; D012709:Serum Albumin / Q000032:analysis; D014429:Twins, Dizygotic; D014807:Vitamin D / Q000031:analogs & derivatives / Q000097:blood
D015415:Biomarkers; C470125:PTH protein, human; D010281:Parathyroid Hormone; D044169:Receptors, Calcium-Sensing; D012709:Serum Albumin; D014807:Vitamin D; C104450:25-hydroxyvitamin D; D002117:Calcitriol; D002118:Calcium