Nutrigenetics & -genomics of Vitamin D and Omega-3 Fatty Acids in Type 1 Diabetes

 描述(申请人提供)：1型糖尿病(T1D)是儿童最常见的慢性疾病之一，其发病率正在增加，可能是由于保护因素的减少。虽然维生素D和omega-3脂肪酸被假设为T1D的保护性饮食因素，但支持它们作用的证据要么相互矛盾，要么缺乏。许多营养流行病学研究依赖于自我报告的饮食摄入量信息，这可能是主观和不准确的，使得很难理解饮食在疾病发展中的作用。迫切需要通过代谢组学分析对膳食摄入量进行独立评估，并需要可靠的预测指标将营养代谢与疾病过程的病因学联系起来。代谢组谱可以作为体内饮食摄入和新陈代谢的独立标志。T1D是一种复杂的慢性疾病，有多种遗传和环境风险因素影响该病自然历史上的关键时间点；因此，有必要将前瞻性收集的饮食数据与饮食生物标记物、代谢物、遗传变异、DNA甲基化和基因表达数据结合起来，以更全面地了解所涉及的途径。例如，目前尚不清楚omega-3脂肪酸和维生素D是否与遗传变异(营养遗传学)相互作用，或者它们是否通过表观基因组学变化(营养基因组学)改变基因表达，以降低胰岛自身免疫(IA)的风险，这是T1D之前的临床前阶段，以及T1D本身。青年糖尿病自身免疫研究(DAISY)对2547名T1D风险增加的儿童进行了研究，在阐明IA和T1D的营养病因方面取得了实质性进展，尽管这突显了关联流行病学工具的复杂性和局限性。我们建议使用DAISY中前瞻性收集的数据进行嵌套病例对照研究。这项研究的总体目标是利用尖端代谢组学、营养遗传学和营养基因组学技术阐明有关维生素D和omega-3脂肪酸的营养流行病学结果以及IA和T1D的风险。我们建议用维生素D结合蛋白(以计算游离的25[OH]D)和与维生素D和omega-3脂肪酸途径相关的代谢物来补充现有的营养和生物标记物数据，以进一步探索T1D的营养流行病学，以便获得独立于自我报告的摄入量的摄入量和营养代谢的评估。然后，我们将通过检查维生素D和omega-3脂肪酸对IA和T1D的影响是否因遗传变异而不同，来探索T1D的营养遗传学。最后，我们将通过研究维生素D和omega-3脂肪酸摄入是否通过表观遗传学改变改变基因表达来影响T1D的易感性，来探索T1D的营养基因组学。在维生素D和omega-3脂肪酸之间的联系以及IA和T1D的发生发展的生物学机制方面，存在着重大的差距。阐明这些机制对于制定旨在减轻T1D负担的预防和治疗策略至关重要。

 DESCRIPTION (provided by applicant): The incidence of type 1 diabetes (T1D), one of the most common chronic diseases of childhood, is increasing, perhaps due to decreases in protective factors. While vitamin D and omega-3 fatty acids have been hypothesized to be protective dietary factors for T1D, the evidence supporting their role is either contradictory or lacking. Many nutrition epidemiology studies rely on self-reported dietary intake information, which can be subjective and inaccurate, making it difficult to understand the role of diet in disease development. There exists a critical need for independent assessment of dietary intake via metabolomics profiling and for reliable predictors that connect nutrient metabolism with the etiology of the disease process. Metabolomic profiling can be used as an independent marker of dietary intake and metabolism within the body. T1D is a complex chronic disease, with multiple genetic and environmental risk factors influencing critical time-points in the disease's natural history; therefore, it is necessary to combine prospectively-collected dietary data with dietary biomarkers, metabolites, genetic variants, DNA methylation and gene expression data in order to more fully understand the pathways involved. For example, it is not known whether omega-3 fatty acids and vitamin D interact with genetic variants (nutrigenetics), or whether they alter gene expression, via epigenomic changes (nutrigenomics), to reduce risk for islet autoimmunity (IA), the pre-clinical phase that precedes T1D, and T1D itself. The Diabetes Autoimmunity Study in the Young (DAISY) cohort of 2,547 children at increased T1D risk has made substantial progress in elucidating the nutritional etiology of IA and T1D, although this has highlighted the complexities of the relationships and limitations of the tools of associational epidemiology. We propose to conduct a nested case-control study using the prospectively collected data in DAISY. The overall aim of the study is to elucidate the nutrition epidemiological findings regarding vitamin D and omega-3 fatty acids and risk of IA and T1D using cutting-edge metabolomics, nutrigenetic and nutrigenomics techniques. We propose to further explore the nutrition epidemiology of T1D by supplementing existing nutrition and biomarker data with vitamin D binding protein (in order to calculate free 25[OH]D), and metabolites related to vitamin D and omega-3 fatty acid pathways, in order to obtain an assessment of intake and nutrient metabolism, independent of self-reported intake. We will then explore the nutrigenetics of T1D by examining whether the effect of vitamin D and omega-3 fatty acids on IA and T1D differs by genetic variation. Finally, we will explore the nutrigenomics of T1D by investigating whether vitamin D and omega-3 fatty acid intake alter gene expression, via epigenetic changes, to influence predisposition to T1D. There are significant gaps in understanding the biologic mechanisms underlying the association between vitamin D and omega-3 fatty acids and the development of IA and T1D. Elucidating these mechanisms is critical for the development of prevention and treatment strategies aimed at reducing the burden of T1D.