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

线粒体处于新陈代谢和免疫的交汇点。线粒体DNA与核 DNA(NDNA)变异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 研究2型糖尿病(T2D)和病毒感染性疾病遗传学的经验丰富的团队 疾病(VID)。提出了一项新的合作，以定义线粒体与和的遗传关联 这两种常见而重要的表型之间的相互作用。最重要的假设是 百万退伍军人计划(MVP)中提供的线粒体遗传信息将与T2D相关 和VID，并将修改它们之间的交互。通过免疫建立重要的机制联系 与VID和T2D发病相关的反应(包括先天反应和获得性反应)部分由 线粒体。冠状病毒病2019(新冠肺炎)是一种新的VID，迄今已感染&gt；60万退伍军人 并突出显示了T2D和VID之间的双向交叉。新冠肺炎包含深刻的免疫力 失调(特别是干扰素信号和反应)，代谢紊乱，包括 T2D的恶化，也因这些情况而变得更加严重。几种与线粒体相关的效应 已经有报道称，新浪新冠肺炎。MVP基因分型目前包括20种常见的和~130种罕见的 在大约650,000名退伍军人中发现了线粒体DNA变异，不久将包括全基因组测序(WGS)和更多 对其中15万名退伍军人进行广泛的mtDNA基因分型。这个项目将描述、策划和派生 通过已建立的和新的方法来建立新的资源，从MVP中的这些变体中获得信息 (“MitoMVP”)并执行新的分析。以下目标将加强对线粒体的了解- 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 加快更广泛的线粒体靶向精准医学努力的资源。首先，MitoMVP，一个策划人 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 将确定数量(mtDNA拷贝数)和质量(预测的致病性)。接下来，线粒体 将识别与T2D和VID相关的遗传信息和nDNA遗传变体，并在基因上 定义了它们之间的相互作用。最后，T2D和VID之间的表型相互作用影响 遗传关联将通过以严重新冠肺炎为原型的分层分析进行评估。 由于T2D是一种复杂的表型，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(如肥胖、高血糖和血脂异常/低高密度脂蛋白 胆固醇)进行分层分析，可能会产生新的关联和重要的机制线索 基因与环境的相互作用。这一目标还将包括对线粒体表型全基因组的关联研究。 (Phewas)以确定感兴趣的新的基因型-表型关联，提供额外的MitoMVP 这些信息将可供其他MVP调查人员未来研究使用。

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.