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

线粒体处于代谢和免疫的交叉点。线粒体DNA（mtDNA）和核 DNA（nDNA）变异影响线粒体功能和退伍军人相关疾病。该项目包括一个 研究2型糖尿病（T2 D）遗传学和病毒感染的丰富经验的团队 疾病（VID）。提出了一项新的合作，以确定线粒体遗传协会与 这两种常见而重要的表型之间的相互作用。首要假设是， 百万退伍军人计划（MVP）中提供的线粒体遗传信息将与T2 D相关 和VID，并将修改它们之间的交互。通过免疫系统的重要机制联系 与VID和T2 D发病机制相关的应答（先天性和适应性）部分由以下调节： 线粒体2019年冠状病毒病（COVID-19）是一种新的VID，迄今已感染超过60万退伍军人 并强调了T2 D和VID之间的双向交叉。COVID-19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 T2 D的恶化，并且这些病症也使其更严重。几种与药物有关的影响 COVID-19已经被报道。MVP基因分型目前包含20种常见和~130种罕见 mtDNA变异在~ 650，000退伍军人，并将很快包括全基因组测序（WGS）与更多 对其中15万名退伍军人进行了广泛的mtDNA基因分型。该项目将表征，策划，并获得 通过已建立的和新的方法从MVP中的这些变体中获得信息，以建立新的资源 （“MitoMVP”）并执行新的分析。以下目的将增进对线粒体的了解- 相关VID和T2 D相互作用，促进新治疗靶点的开发，并提供数据 资源，以加速更广泛的针对性的精准医疗工作。首先，MitoMVP，一个精心策划的 MVP中的线粒体遗传信息数据集，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T2 D和VID相关的遗传信息和nDNA遗传变异， 它们之间的相互作用被定义。最后，T2 D和VID之间的表型相互作用， 将通过以严重COVID-19为原型的分层分析评估遗传关联。 由于T2 D是一种复杂的表型，MVP中的信息将用于定义T2 D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重要线索的机制， 基因与环境的相互作用这一目标还将包括线粒体全表型关联研究 （PheWAS），以确定新的感兴趣的基因型-表型关联，提供额外的MitoMVP 其他MVP研究者可用于未来研究的信息。

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.