Defining the Contribution of Mitochondrial DNA to Viral Infectious Diseases, Type 2 Diabetes, and their Interactions

确定线粒体 DNA 对病毒传染病、2 型糖尿病及其相互作用的作用

• 批准号: 10589249
• 负责人: TODD M HULGAN
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589249
• 关键词: Acceleration; Accounting; Address; Affect; Atlases; Bioenergetics; COVID-19; COVID-19 impact; Clinical; Collaborations; Communicable Diseases; Complex; Custom; DNA; Data; Data Set; Development; Diabetes Mellitus; Disease; Dyslipidemias; Future; Genes; Genetic; Genetic Variation; Genetic study; Genotype; Health; High Density Lipoprotein Cholesterol; Hyperglycemia; Immune; Immune response; Immunity; Infection; Inflammation; Innate Immune Response; Interferon Type I; Interferons; Laboratories; Link; Measures; Metabolic; Metabolism; Methods; Mitochondria; Mitochondrial DNA; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Obesity; Pathogenesis; Pathogenicity; Phenotype; Regulation; Reporting; Research; Research Personnel; Resources; Risk; Signal Transduction; Subgroup; Variant; Veterans; Viral; Virus Diseases; Work; data resource; defined contribution; diabetes risk; disorder risk; experience; gene environment interaction; genetic association; genetic information; genetic variant; genome sequencing; immune activation; innovation; interest; metabolic phenotype; new therapeutic target; novel; phenome; precision medicine; prevent; programs; prototype; response; severe COVID-19; whole genome

Mitochondria are at the intersection of metabolism and immunity. Mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) variants affect mitochondrial function and diseases relevant to Veterans. This project includes a team with extensive experience studying the genetics of type 2 diabetes mellitus (T2D) and viral infectious diseases (VID). A new collaboration is proposed to define the mitochondrial genetic associations with and interactions between these two common and important phenotypes. The overarching hypothesis is that mitochondrial genetic information available in the Million Veteran Program (MVP) will be associated with T2D and VID, and will modify interactions between them. Important mechanistic connections through immune responses (both innate and adaptive) relevant for VID and T2D pathogenesis are regulated in part by mitochondria. Coronavirus disease 2019 (COVID-19) is a new VID that has infected >600,000 Veterans to date and highlights the bi-directional intersection between T2D and VID. COVID-19 includes profound immune dysregulation (particularly interferon [IFN] signaling and responses), metabolic derangements including exacerbation of T2D, and is also made more severe by these conditions. Several mitochondria-related effects of COVID-19 have already been reported. MVP genotyping currently contains 20 common and ~130 rare mtDNA variants in ~650,000 Veterans and will soon include whole genome sequencing (WGS) with more extensive mtDNA genotyping for 150,000 of these Veterans. This project will characterize, curate, and derive information from these variants in the MVP by established and novel methods to establish a new resource (“MitoMVP”) and perform new analyses. The following aims will enhance the understanding of mitochondria- related VID and T2D interactions, facilitate development of new therapeutic targets, and provide a data resource to accelerate broader mitochondria-targeted precision medicine efforts. First, MitoMVP, a curated dataset of mitochondrial genetic information in the MVP including expanded mitochondrial genetic information on quantity (mtDNA copy number) and quality (predicted pathogenicity) will be established. Next, mitochondrial genetic information and nDNA genetic variants associated with T2D and VID will be identified, and genetic interactions between them defined. Finally, phenotypic interactions between T2D and VID that influence genetic associations will be assessed through stratified analyses focused on severe COVID-19 as a prototype. Because T2D is a complex phenotype, information in the MVP will be used to define subgroups with T2D- related clinical and laboratory metabolic phenotypes (e.g., obesity, hyperglycemia, and dyslipidemia/low HDL cholesterol) for stratified analyses, potentially yielding new associations and important clues to mechanisms of gene-by-environment interactions. This aim will also include mitochondrial phenome-wide association studies (PheWAS) to identify novel genotype-phenotype associations of interest, providing additional MitoMVP information that will be available for future studies by other MVP investigators.

线粒体在代谢和免疫学的交集处。线粒体DNA（mtDNA）和核 DNA（NDNA）变体会影响线粒体功能和与退伍军人相关的疾病。该项目包括一个 具有研究2型糖尿病（T2D）和病毒感染性的遗传学的丰富经验的团队 疾病（vid）。提出了一项新的合作，以定义与线粒体遗传关联和 这两种常见和重要表型之间的相互作用。总体假设是 百万退伍军人计划（MVP）中可用的线粒体遗传信息将与T2D相关联 和vid，并将修改它们之间的相互作用。通过免疫的重要机械连接 与VID和T2D发病机理相关的反应（既有和自适应）部分受 线粒体。冠状病毒疾病2019（Covid-19）是一种新的VID，迄今已感染了> 60万退伍军人 并突出了T2D和VID之间的双向交集。 Covid-19包括深刻的免疫力 失调（部分干扰素[IFN]信号传导和响应），代谢发展包括 T2D加剧，并且由于这些条件而变得更加严重。几种与线粒体相关的作用 COVID-19的据报道。 MVP基因分型目前包含20个常见，〜130罕见 〜650,000名退伍军人的mtDNA变体，很快将包括整个基因组测序（WGS） 这些退伍军人中有150,000人广泛的mtDNA基因分型。该项目将表征，策划和得出 通过建立新的方法来建立新资源，来自MVP中这些变体的信息 （“ mitoMVP”）并执行新的分析。以下目的将增强对线粒体的理解 - 相关的VID和T2D相互作用，有助于开发新的治疗靶标，并提供数据 加速更广泛的线粒体精确医学工作的资源。首先，mitomvp，策划 MVP中线粒体遗传信息的数据集，包括扩展的线粒体遗传信息 将建立数量（mtDNA拷贝数）和质量（预测的致病性）。接下来，线粒体 将鉴定与T2D和VID相关的遗传信息和NDNA遗传变异，并遗传 它们之间的相互作用已定义。最后，T2D与VID之间的表型相互作用 遗传关联将通过针对严重的Covid-19作为原型的分层分析进行评估。 由于T2D是一种复杂的表型，因此MVP中的信息将用于定义具有T2D-的亚组 相关的临床和实验室代谢表型（例如肥胖，高血糖和血脂异常/低HDL 胆固醇）用于分层分析，有可能产生新的关联和重要的线索 基因与环境相互作用。这个目标还将包括线粒体现象的关联研究 （PHEWAS）确定有趣的基因型 - 表型关联，提供其他MitoMVP 其他MVP调查人员将来可以使用的信息。