Vitamin D receptor gene polymorphisms: Analysis of ligand binding and hormone responsiveness in cultured skin fibroblasts
Vitamin D receptor gene polymorphisms: Analysis of ligand binding and hormone responsiveness in cultured skin fibroblasts
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DOI：
10.1006/bbrc.1997.7986
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发表时间：
1998-01-26
影响因子：
3.1
通讯作者：
Feldman, D
中科院分区：
文献类型：
--
作者：
Gross, C;Musiol, IM;Feldman, D
最近的报告表明，编码维生素D受体（VDR）的基因多态性决定了骨矿物质密度（BMD）的遗传贡献的一部分。已经发现，在外显子8和9之间的内含子中缺少Bsm I限制性位点的等位基因的纯合个体（BB基因型）具有比具有Bsm I位点的等位基因的纯合个体（bb基因型）更低的BRID。有趣的是，这种多态性也与前列腺癌风险相关。观察到的BMD和前列腺癌风险的变化可能是由于VDR功能或丰度的改变导致靶细胞对1，25-二羟基维生素D-3 [1，25（OH）（2）D-3]作用的不同反应性。为了验证这一假设，我们培养了来自具有BE、Bb和bb基因型的供体的真皮成纤维细胞，并测定了VDR表达水平和对1，25（OH）（2）D-3处理的细胞反应性，与bb细胞相比，BB细胞中的VDR丰度、对[H-3] 1，25（OH）（2）D-3的亲和力和VDR mRNA水平没有可检测到的差异。通过逆转录-聚合酶链反应（RT-PCR）检测来自Bb成纤维细胞的mRNA上的两种VDR基因等位基因的相等表达。在剂量反应实验中，通过诱导24-羟化酶mRNA评估的成纤维细胞对1，25（OH）（2）D-3的反应性在BE和bb细胞类型之间相似。虽然我们测量的参数存在个体差异，但我们培养的真皮成纤维细胞的小样本的平均值没有可检测或一致的差异。总之，我们没有检测到与VDR基因型相关的VDR特性或细胞对1，25（OH）（2）D-3的反应性的显著差异。我们的研究结果表明，这些多态性不影响VDR功能，而是可能是负责骨质疏松症和前列腺癌风险的基因型相关变异的附近基因的标志物。(C)北京：科学出版社.
Recent reports have suggested that polymorphisms in the gene encoding the vitamin D receptor (VDR) determine a portion of the genetic contribution to bone mineral density (BMD). Individuals homozygous for the allele lacking the Bsm I restriction site in the intron between exons 8 and 9 (BB genotype) have been found to have lower BRID than individuals homozygous for the allele having the Bsm I site (bb genotype). Interestingly, this polymorphism has also been associated with prostate cancer risk, The observed changes in BMD and prostate cancer risk might be due to an alteration in the function or abundance of the VDR leading to differential responsiveness of target cells to the action of 1,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3]. To test this hypothesis, we cultured dermal fibroblasts from donors with BE, Bb, and bb genotypes and determined the level of VDR expression and the cellular responsiveness to 1,25(OH)(2)D-3 treatment, VDR abundance, affinity for [H-3]1,25(OH)(2)D-3, and VDR mRNA levels were not detectably different in BB cells compared to bb cells, Moreover, equal expression of both VDR gene alleles was detected by reverse transcriptase - polymerase chain reaction (RT-PCR) on mRNA from Bb fibroblasts. Fibroblast responsiveness to 1,25(OH)(2)D-3, assessed by induction of 24-hydroxylase mRNA, was similar between BE and bb cell types in dose-response experiments. Although there were individual variations in the parameters we measured, there were no detectable or consistent differences in mean values from our small sample of cultured dermal fibroblasts. In conclusion, we did not detect significant differences in VDR properties or cellular responsiveness to 1,25(OH)(2)D-3 that correlated with VDR genotype, Our findings suggest that these polymorphisms do not affect VDR function, but rather may be a marker for a nearby gene that is responsible for the genotype-associated variation in osteoporosis and prostate cancer risk. (C) 1998 Academic Press.