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 DNA (mtDNA) 和核 DNA (nDNA) 变异影响线粒体功能和与退伍军人相关的疾病。 团队在研究 2 型糖尿病 (T2D) 和病毒感染的遗传学方面拥有丰富的经验 提出了一项新的合作来定义线粒体与 和 的遗传关联。 这两种常见且重要的表型之间的相互作用。 百万退伍军人计划 (MVP) 中提供的线粒体遗传信息将与 T2D 相关 和 VID，并将通过免疫改变它们之间的重要机制连接。 与 VID 和 T2D 发病机制相关的反应（先天性和适应性）部分受 2019 年冠状病毒病 (COVID-19) 是一种新的 VID，迄今为止已感染超过 600,000 名退伍军人。 并强调 T2D 和 VID 之间的双向交叉包括深刻的免疫。 失调（特别是干扰素 [IFN] 信号传导和反应）、代谢紊乱，包括 T2D 恶化，并且这些条件也使线粒体相关的影响变得更加严重。 目前已报道了 20 种常见的 MVP 基因分型和约 130 种罕见的 MVP 基因分型。 大约 650,000 名退伍军人中存在 mtDNA 变异，并且很快将包括全基因组测序 (WGS) 以及更多 该项目将对其中 150,000 名退伍军人进行广泛的 mtDNA 基因分型，并进行表征、策划和衍生。 通过已建立的新颖方法从 MVP 中的这些变体中获取信息来建立新资源 （“MitoMVP”）并进行新的分析，以下目标将增强对线粒体的理解- 相关的 VID 和 T2D 相互作用，促进新治疗靶点的开发，并提供数据 首先，MitoMVP，一个精心策划的资源。 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 接下来，将确定线粒体的数量（线粒体DNA拷贝数）和质量（预测的致病性）。 将鉴定与 T2D 和 VID 相关的遗传信息和 nDNA 遗传变异，并进行遗传分析 最后，定义了影响 T2D 和 VID 之间的表型相互作用。 将通过以重症 COVID-19 为原型的分层分析来评估遗传关联。 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）进行分层分析，可能产生新的关联和机制的重要线索 该目标还将包括线粒体表型范围的关联研究。 (PheWAS) 识别感兴趣的新基因型-表型关联，提供额外的 MitoMVP 其他 MVP 研究人员可用于未来研究的信息。