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

VDR基因型对维生素D在肝硬化中免疫作用的影响

• 批准号: 501462732
• 负责人: Professor Dr. Christian Lange
• 金额: --
• 依托单位: Medizinische Klinik und Poliklinik II - Großhadern
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/501462732?language=en
• 关键词: Role; VDR; genotype; immunological; effects

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.

维生素D具有多效性的生物学作用，如调节先天性和适应性免疫反应。然而，维生素D补充剂对大多数临床终点没有证明的益处。然而，亚组分析表明，补充维生素D的益处可能取决于个体VDR基因型。我们可以显示骨化三醇类似物对VDR构象和连续基因转录的差异影响，尽管在这些研究中尚未考虑VDR基因型。我们假设，考虑到个体VDR基因型，个体化维生素D治疗可能比一般人群中的维生素D补充剂更有前途，并且骨化三醇类似物可能对胆钙化醇/骨化三醇无反应的个体有益。为了检验这一假设，应进行遗传相关性研究，以表征肝硬化的结局以及肝硬化患者的免疫表型（取决于VDR基因型）。在体外实验中，将评估骨化三醇类似物对这些患者免疫细胞的影响与遗传VDR背景的关系。此外，还将尝试确定VDR中潜在的致病遗传变异。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，这可能为肝硬化患者进一步个体化维生素D治疗提供基础。