Uitterlinden André G, Fang Yue, van Meurs Joyce B J, van Leeuwen Hans, Pols Huibert A P
Department of Internal Medicine, Erasmus University Rotterdam Medical Centre, P.O. Box 1738, Genetic Laboratory, Room Ee575, NL-3000 DR Rotterdam, The Netherlands.
J Steroid Biochem Mol Biol. 2004 May;89-90(1-5):187-93. doi: 10.1016/j.jsbmb.2004.03.083.
The role in skeletal metabolism of the steroid hormone Vitamin D and its nuclear receptor (VDR) is well known. In addition, however, Vitamin D is also involved in a wide variety of other biological processes including modulation of the immune response and regulation of cell proliferation and differentiation. Variations in the Vitamin D endocrine system have thus been linked to several diseases, including osteoarthritis, diabetes, cancer, cardiovascular disease and tuberculosis. Evidence to support this pleiotropic character of Vitamin D has included epidemiological studies on circulating Vitamin D hormone levels, but also genetic epidemiological studies. Genetic studies provide excellent opportunities to link molecular insights with epidemiological data and have therefore gained much interest. DNA sequence variations which occur frequently in the population are referred to as "polymorphisms" and are usually suspected of having only modest and subtle effects. Recent studies have indicated many polymorphisms to exist in the VDR gene, but the influence of VDR gene polymorphisms on VDR protein function are largely unknown. Sofar, three adjacent restriction fragment length polymorphisms (RFLP) for BsmI, ApaI and TaqI, respectively, at the 3' end of the VDR gene have been the most frequently studied sofar. But because these polymorphisms are probably non-functional, linkage disequilibrium (LD) with one or more truly functional polymorphisms elsewhere in the VDR gene is assumed to explain the associations observed. Research is therefore focussed on documenting additional polymorphisms across the VDR gene to verify this hypothesis, and on trying to understand the functional consequences of the variations. Substantial progress has been made including the discovery of novel polymorphisms in the large promoter region of the VDR gene. Eventually, results of this research will deepen our understanding of variability in the Vitamin D endocrine system and might find applications in risk-assessment of disease and in predicting response-to-treatment.
类固醇激素维生素D及其核受体（VDR）在骨骼代谢中的作用已广为人知。然而，除此之外，维生素D还参与多种其他生物学过程，包括免疫反应的调节以及细胞增殖和分化的调控。因此，维生素D内分泌系统的变化已与多种疾病相关联，包括骨关节炎、糖尿病、癌症、心血管疾病和结核病。支持维生素D这种多效性特征的证据不仅包括关于循环维生素D激素水平的流行病学研究，还包括遗传流行病学研究。遗传研究为将分子见解与流行病学数据联系起来提供了绝佳机会，因此备受关注。在人群中频繁出现的DNA序列变异被称为“多态性”，通常被认为只具有适度和微妙的影响。最近的研究表明VDR基因中存在许多多态性，但VDR基因多态性对VDR蛋白功能的影响在很大程度上尚不清楚。迄今为止，VDR基因3'端分别针对BsmI、ApaI和TaqI的三个相邻限制性片段长度多态性（RFLP）是迄今为止研究最频繁的。但由于这些多态性可能无功能，因此假定与VDR基因其他位置的一个或多个真正有功能的多态性存在连锁不平衡（LD）来解释所观察到的关联。因此，研究集中在记录VDR基因上更多的多态性以验证这一假设，并试图了解这些变异的功能后果。已经取得了实质性进展，包括在VDR基因的大启动子区域发现了新的多态性。最终，这项研究的结果将加深我们对维生素D内分泌系统变异性的理解，并可能在疾病风险评估和预测治疗反应中得到应用。
