Ancestry-Specific Genetic Influences and Potential Therapeutics for Ocular Disorders in the Million Veteran Program

Background and Innovation. The ability of Veterans to retain independence depends on their ability to perform visual tasks such as reading and driving. This independence is threatened by ocular disorders such as age-related macular degeneration (AMD) that result in central vision loss and are prevalent in the Veteran population. We currently lack a complete understanding of the risk factors that contribute to AMD onset and the basis for their marked variation between Veterans of European (EUR) or African (AFR) ancestry. Currently, we have insufficient treatment options to offer Veterans with AMD to slow or stop disease progression and vision loss. The VA Million Veteran Program (MVP) provides a powerful resource to address these shortcomings, by providing genetic data in the context of the de-identified but otherwise complete electronic health record (EHR) and other MVP-specific instruments (e.g., lifestyle survey). MVP is one of the largest biobanks in the world, with more than 1 million Veterans having been enrolled to date. Importantly, MVP has enrolled substantial numbers of Veterans of AFR and EUR ancestry, providing the opportunity to follow on our original observation that genetic variants that confer strong risk in EUR populations do have a comparable impact on individuals of AFR ancestry. MVP now provides whole genome sequence data for a considerable number of Veterans, which provide a critical next step to understand ancestry-specific differences in AMD risk. Aim 1 will use these to data to understand observations made during the current award period that alleles for genes such as CFH, which make strong contributions to risk for age-related macular degeneration (AMD) in EUR cohorts, are not linked to AMD in AFR populations. In Aim 2 we will use the MVP EHR data to determine if drugs already used in the care of Veterans impact AMD risk. We will follow our proven model wherein we documented that metformin decreases risk for AMD in both EUR and AFR Veterans. Significance and Impact to Veterans Healthcare. This project will (a) identify risk factors that drive AMD pathogenesis in diverse populations, thereby providing tools for early identification of the disease state based on EHR and genetic data and (b) identify medications already in the VA formulary that impact AMD risk. Path to Translation/Implementation. This project will provide a roadmap for early and effective diagnosis across the diverse ancestries that comprise the U.S. Veteran population. This project will provide insights into new therapeutic approaches for AMD, which can be rapidly incorporated into future clinical trials. Project Number: 1I01BX006444-01A2 | Fiscal Year: 2025 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: NEAL PEACHEY (+1 co-PI) | Institution: LOUIS STOKES CLEVELAND VA MEDICAL CENTER, CLEVELAND, OH | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 NURF-H (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11053997