The VA Eosinophilic Esophagitis Million Veteran Program (VA EoE-MVP) Cohort for Clinical, Environmental, and Genetic Epidemiology

Eosinophilic esophagitis (EoE) is a chronic allergen/immune-mediated disease of the esophagus affecting approximately 1 out of every 2,500 persons. EoE incidence and prevalence are dramatically rising in the United States (US) and globally, and it is unclear what triggers or factors are contributing to these trends. Previous epidemiologic studies of EoE have been challenged by small sample sizes and, therefore, the ability to robustly measure and evaluate specific clinical, environmental, and genetic etiologic factors associated with EoE development and disease progression. Large, validated cohort studies with access to environmental data that can be analyzed in conjunction with genomic and clinical data, such as comorbid information, pharmacologic data, procedure and histology reports, and other outcomes data, are critical to address EoE epidemiology knowledge gaps and advance science and discovery in EoE. The Veterans Health Administration (VHA) data infrastructure is the ideal system to study the epidemiology and genetic underpinnings of EoE as it contains robust databases, namely the Corporate Data Warehouse (CDW) and the Million Veteran Program (MVP), which comprise clinical, environmental, and genetic information for thousands of Veterans with a diagnosis of EoE. VHA data have been leveraged to create one of the largest [and diverse] research cohorts of individuals with EoE (n=6,637), termed the VA eosinophilic esophagitis cohort (VA E-O-ECHO). Use of this cohort is proposed to perform observational studies and identify risk factors associated with EoE diagnosis and disease outcomes. Furthermore, this cohort creation strategy will be extended to develop a validated research cohort using VA MVP data, the EoE-MVP cohort. Case-control genome-wide association studies (GWASs) will be performed using the EoE-MVP cohort to identify significant risk loci associated with EoE diagnosis and severe disease phenotypes. Structured environmental survey responses from the EoE-MVP cohort will be used to investigate deployment and line-of-duty environmental exposures associated with EoE. The overarching goal of this research proposal is to organize structured and unstructured big data within the CDW and MVP to evaluate risk factors for EoE and EoE disease outcomes, and ultimately improve the understanding of [EoE pathogenesis and natural history to improve clinical care.] The specific aims for this project are to: (1) Identify clinical and environmental factors associated with EoE. Associations between clinical/environmental factors and EoE diagnosis will be examined using usual healthcare data (CDW) and drawing from detailed MVP surveys, utilizing a large sample case-control design. (2) Identify genetic factors associated with EoE diagnosis using the MVP. MVP genomic data will be leveraged to conduct GWASs and GWAS meta-analyses for EoE. Genetic architecture of EoE will be characterized by performing genetic correlations studies using associated atopic conditions such as asthma and atopic dermatitis. Genetically correlated phenotypes will be used to perform multi-trait analysis of GWAS and boost statistical power for risk loci discovery for EoE. Lastly, gene set enrichment analyses will be performed to study biological processes/pathways underlying EoE. [(3) Identify clinical, environmental, and genetic factors associated with EoE treatment response and other outcomes. Disease natural history of every individual with EoE in the MVP will be mapped using robust clinical data, including objective endoscopic and histologic findings. Associations between clinical, environmental, and genetic factors and EoE outcomes will be examined using case-control studies. Fundamentally, this work will serve as a hypothesis-generating launchpad for the principal investigator and others to advance science and clinical management in EoE and improve health and well-being for individuals with EoE. For example, we anticipate establishing prospective randomized Project Number: 1IK2BX006572-01A1 | Fiscal Year: 2025 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Eric Low | Institution: VA SAN DIEGO HEALTHCARE SYSTEM, SAN DIEGO, CA | Activity Code: IK2 | Study Section: Special Emphasis Panel[ZRD1 GAST-L (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11043820