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

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.