Inferring effects of vitamin D-related gene polymorphisms and gene expressions on blood vitamin D concentrations, immune response and health in dairy cows

奶牛在泌乳早期经历负能量平衡，这意味着免疫抑制和疾病易感性的风险增加。维生素D是参与相应生理功能和途径的重要代谢物，建议从营养角度进行详细评估，并通过饲料有针对性地补充维生素D。维生素D调控的遗传方面主要是在人类中推断出来的。在奶牛中，基因变异、血液维生素D水平和健康之间的关系尚不清楚，但为优化育种策略以提高免疫状态和抗病能力提供了重要的见解。申请人Eder教授和König教授都发现了CYP2R1基因多态性与奶牛血液维生素D水平和疾病之间的关联。这种对维生素D遗传机制的首次洞察表明，利用密集的基因组序列来识别潜在的基因变异和维生素D代谢的途径，并推断奶牛健康的进一步因果关系。因此，本项目旨在通过非常详细的靶点富集（50倍覆盖率）霰弹枪测序，鉴定16个维生素D代谢相关基因的遗传多态性，并研究多态性对奶牛维生素D代谢物浓度、疾病发生和免疫反应的影响。在这方面，我们将重点关注具有挑战性的哺乳期早期血液维生素D的测量，深层健康特征记录，免疫参数测量，基因组测序和基因表达，考虑300头德国荷斯坦奶牛饲养在两个研究群中，并确定了个体饲养的可能性。在两个奶牛群中，奶牛将被分配到维生素D补充水平不同的两个喂养组。我们推测，参与维生素D代谢的基因多态性、各自的转录组谱及其与饲养、免疫反应和产奶遗传优势群的相互作用显著影响奶牛维生素D代谢和疾病发生。对于研究牛群以及来自合同牛群的约20,000头奶牛，（估算的）WGS数据（覆盖率为30倍）已经可用。现有的WGS数据将用于免疫反应指标和疾病的全基因组关联。最后，我们将特定疾病的关联信号与免疫措施的关联信号进行了比较，表明a)可作为免疫标记的健康特征，以及b)与基因组预测具有特定相关性的snp和染色体片段。此外，基因表达分析（表达QTL）的结果将在增强基因组预测中得到考虑。

Dairy cows experience a negative energy balance in early lactation, implying an increased risk for immunosuppression and disease susceptibility. An important metabolite involved in corresponding physiological functions and pathways is vitamin D, suggesting detailed evaluations from a nutritional perspective and targeted vitamin D supplementation via feed. Genetic aspects of vitamin D regulations mostly have been inferred in humans. In dairy cows, the relationships between genetic variants, blood vitamin D levels and health are unknown, but provide essential insights to optimise breeding strategies for an improved immune status and disease resistance. Both applicants Prof. Eder and Prof. König identified associations between polymorphisms of the CYP2R1 gene with blood vitamin D levels and diseases in dairy cows. Such first insights into genetic vitamin D mechanisms suggest utilisation of dense genome sequences to identify the underlying genetic variants and pathways involved in vitamin D metabolism, and to infer further causalities with cow health. Therefore, the project aims at the identification of genetic polymorphisms of 16 genes involved in vitamin D metabolism using very detailed shotgun sequencing with target enrichment (50x coverage), and to study effects of polymorphisms on vitamin D metabolite concentrations, disease occurrence and immune response in dairy cows. In this regard, we will focus on measurements of blood vitamin D during the challenging early lactation period, on deep health trait recording, on immune parameter measurements, genome sequencing and gene expressions considering 300 German Holstein dairy cows kept in two research herds with established individual feeding possibilities. In both herds, the cows will be allocated into two feeding groups with different vitamin D supplementation levels. We hypothesize that polymorphisms in genes involved in vitamin D metabolism, the respective transcriptomic profiles and their interactions with feeding, immune response and genetic merit groups for milk yield significantly affect vitamin D metabolism and disease occurrence in dairy cows. For the research herd cows as well as for ~20,000 cows from contract herds, (imputed) WGS data (30x coverage) is already available. The existing WGS data will be used for genome-wide associations for immune response indicators and for diseases. Finally, we compare association signals for the specific diseases with association signals for immunity measures, indicating a) health traits, which can be used as immunity markers, and b) SNPs and chromosome segments with specific relevance for genomic predictions. Additionally, results from gene expression analyses (expression QTL) will be considered in enhanced genomic predictions.