Role of VDR-genotype for immunological effects of vitamin D in liver cirrhosis

维生素D具有多种生物学效应，如调节先天免疫反应和获得性免疫反应。然而，维生素D补充剂在大多数临床终点并没有得到证实的益处。然而，亚组分析表明，补充维生素D的益处可能取决于个体的VDR基因。我们可以显示骨化三醇类似物对VDR的构象和连续基因转录的不同影响，尽管在这些研究中没有考虑VDR基因。我们假设，在一般人群中，考虑到个体VDR基因，个体化维生素D治疗可能比补充维生素D更有前景，骨化三醇类似物可能对对胆钙素/骨化三醇无反应的个体有益。为了验证这一假设，应该进行一项遗传关联研究，以确定肝硬变的结局以及与VDR基因相关的肝硬变患者的免疫表型。在体外实验中，骨化三醇类似物对这些患者免疫细胞的影响将根据遗传VDR背景进行评估。此外，还将尝试确定VDR中潜在的因果遗传变异。总之，这些实验将根据个体遗传VDR背景全面了解骨化三醇及其类似物的生物学作用，这可能为进一步对肝硬变患者进行个体化维生素D治疗提供基础。

Vitamin D has pleiotropic biological effects like modulation of innate and adaptive immune responses. Yet, vitamin D supplementation has no proven benefit on most clinical endpoints. However, subgroup analysis suggest that the benefit of vitamin D supplementation may depend on the individual VDR genotype. We could show a differential impact of calcitriol-analogs on the conformation of the VDR and consecutive gene transcription, though VDR genotype has not been considered in these investigations. We hypothesize, that individualized vitamin D therapy, taking into account the individual VDR genotype, may be more promising than vitamin D supplementation in the general population, and that calcitriol-analogs may be beneficial in individuals not responding to cholecalciferol/calcitriol. To test this hypothesis, a genetic association study shall be performed characterizing the outcome of liver cirrhosis as well as the immunophenotype of patients with liver cirrhosis in dependence of the VDR genotype. In ex vitro experiments, the impact of calcitriol-analogs on immune cells of these patients will be assessed in relationship to the genetic VDR background. Furthermore, an attempt will be made to identify the underlying causal genetic variant in the VDR. Collectively, these experiments shall result in a comprehensive understanding of the biological action of calcitriol and its analogs according to the individual genetic VDR background, which may provide a basis for further individualized vitamin D therapy in patients with liver cirrhosis.