Functional characterization of calcium sensing receptor polymorphisms and absence of association with indices of calcium homeostasis and bone mineral density
Functional characterization of calcium sensing receptor polymorphisms and absence of association with indices of calcium homeostasis and bone mineral density
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DOI：
10.1111/j.1365-2265.2006.02634.x
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发表时间：
2006-11-01
影响因子：
3.2
通讯作者：
Thakker, Rajesh V.
中科院分区：
文献类型：
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作者：
Harding, Brian;Curley, Alan J.;Thakker, Rajesh V.
目的研究钙敏感受体(CaSR)基因多态性与血钙、甲状旁腺素(PTH)和骨密度(BMD)的关系。然而，其他三项研究未能发现这种联系。因此，我们进一步研究了三个CaSR编码区(Ala986Ser、Arg990Gly和Gln1011Glu)多态与钙稳态和骨密度指标以及受体功能改变的关系。患者和设计调查了110对成人、高加索人、女性、双卵双生子，研究这三个CaSR多态与血钙、白蛋白、甲状旁腺素、25-羟基维生素D-3(25OHD(3))、1，25-二羟基维生素D-3[1，25(OH)2 D3]、尿钙排泄和骨密度的关系。结果经白蛋白、甲状旁腺激素、25OHD(3)、1，25(OH)(2)D-3、尿钙排泄量或髋部、前臂和腰椎骨密度校正后的血钙水平与CaSR基因无关联。这些发现得到了CaSR变异体在剂量-反应曲线上的功能差异的支持，野生型(Ala986/Arg990/Gln1011)、Ser986、Gly990和Glu1011 CaSR变异体的EC50值(平均值+/-扫描电子显微镜)为2.74+/-0.29m、3.09+/-0.34m(P>；0.4)、2.99+/-0.23m(P>；0.4)和2.96+/-0.30m(P>；0.4)。结论我们的研究足以检测到可解释高达5%但不低于1%的变异的效应。我们的研究表明，编码区的三个CaSR多态对该女性群体的钙稳态指数没有重大影响，也不会改变受体功能。
Objectives 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.Patients and design 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 EC50 values (mean +/- SEM) of the wild-type (Ala986/Arg990/Gln1011), Ser986, Gly990 and Glu1011 CaSR variants being 2.74 +/- 0.29 m., 3.09 +/- 0.34 m. ( P > 0.4), 2.99 +/- 0.23 m. (P > 0.4) and 2.96 +/- 0.30 m. ( 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.