Leveraging the Million Veteran Program Infrastructure and Data for a Rapid Research Response to COVID-19

Stacey B. Whitbourne, PhD Jennifer Moser, PhD Kelly Cho, PhD, MPH Jennifer Deen Lori L. Churby Amy C. Justice, MD, PhD Juan P. Casas, MD, PhD Saiju Pyarajan, PhD Phil S. Tsao, PhD J. Michael Gaziano, MD, MPH Sumitra Muralidhar, PhD

Disclosures

Fed Pract. 2023;40(5):s23-S28.

Abstract and Introduction

Abstract

Background: The Veterans Health Administration Office of Research and Development (ORD) played a key role in the federal government’s response to the COVID-19 pandemic. The ORD effectively leveraged existing resources to answer questions related to the SARS-CoV-2 virus and COVID-19.

Observations: When the COVID-19 pandemic hit in 2020, the Million Veteran Program (MVP), one of the largest genomic cohorts in the world, extended the centralized recruitment and enrollment infrastructure to develop a COVID-19 research volunteer registry to assist enrollment in the vaccine and treatment trials in which the US Department of Veterans Affairs (VA) participated. In addition, the MVP allowed for new data collection and a large genomic cohort to understand host contributions to COVID-19. This article describes ways the MVP contributed to the VA’s rapid research response to COVID-19. Several host genetic factors believed to play a role in the development and severity of COVID-19 were identified. Furthermore, existing MVP partnerships with other federal agencies, particularly with the Department of Energy, were leveraged to improve understanding and management of COVID-19.

Conclusions: A previously established enterprise approach and research infrastructure were essential to the VA’s successful and timely COVID-19 research response. This infrastructure not only supported rapid recruitment in vaccine and treatment trials, but also leveraged the unique MVP and VA electronic health record data to drive rapid scientific discovery and inform clinical operations. Extending the models that VA research applied to the federal government at large and establishing centralized resources for shared or federated data analyses across federal agencies will better equip the nation to respond to future public health crises.

Introduction

The Million Veteran Program (MVP) was launched in 2011 by the US Department of Veterans Affairs (VA) to enroll at least 1 million veterans in a longitudinal cohort to better understand how genes, lifestyle, military experience, and environmental exposures interact to influence health and illness and ultimately enable precision health care. The MVP has established a national, centralized infrastructure for recruitment and enrollment, biospecimen and data collection and storage, data generation and curation, and secure data access. When the COVID-19 pandemic hit in 2020, the MVP was leveraged to support research utilizing the following key infrastructure components: (1) MVP recruitment and enrollment platform to provide support for COVID-19 vaccine and treatment trials and to collect COVID-19 data from MVP participants; (2) using MVP Phenomics for COVID-19 research data cleaning and curation, assisting with the development of a VA Severity Index for COVID-19, and forming 6 scientific working groups to coordinate COVID-19 research questions; and (3) the VA/MVP and US Department of Energy (DOE) partnership to assist in responding to COVID-19 research questions identified by the US Food and Drug Administration (FDA). This article describes these infrastructure components in more detail and highlights key findings from the MVP COVID-19 research efforts.

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Table MVP COVID-19 Working Group Primary Objectives, Key Findings, and Implications
Working group	Primary objectives	Key findings	Implications
Druggable genome	Examine drug-repurposing opportunities for COVID-19 prevention; hospitalized patient severity/complications	Angiotensin-converting enzyme 2, IFNAR2, and IL10RB identified as potential targets for early COVID-19 management⁴	Among the first to determine the role of IFN as part of the immune response to COVID-19
Pharmacogenomics	Risk variants of AKI and mortality among Black veterans with COVID-19; remdesivirinduced liver chemistry abnormalities pharmacogenetic analysis	MVP Black participants hospitalized for COVID-19 with specific APOL1 variants associated with higher risks of AKI, AKI severity, and death, even for individuals with prior normal kidney function⁵	APOL1 variants associated with increased risk of AKI among Black veterans hospitalized with COVID-19
Disease mechanisms	Specific genetic markers and effects on COVID-19 including: polygenic predisposition to VTE; COVID-19–positive SCT carrier outcomes; mucin 5B, oligomeric mucus/gel-forming gene polymorphism; COVID-19 infection protective effects	SCT associated with increased death following COVID-19⁶; common variant in a mucoprotein gene associated with idiopathic pulmonary fibrosis (present in about 20% of the population) associated with fewer COVID-19 infection hospitalizations and pneumonia events⁷	SCT (present in 8% of Black individuals) is complicating factor in COVID-19 infection and associated with increased death following COVID-19; common variant in a mucoprotein gene associated with fewer hospitalizations and pneumonia events COVID-19 infection and may be protective
Genomics for risk prediction, PRS, and Mendelian randomization	How genetic information can enhance COVID-19 risk prediction including: blood group typing and protective effects on COVID-19 infection; PRS/human leukocyte antigen typing and COVID-19 outcomes; transcriptome-wide association study of COVID-19–positive participants	In 20,000 COVID-19 cases of a racially diverse group of MVP participants, 4 independent genetic variants identified that contributed to COVID-19 positivity, including a novel locus exclusively among Hispanic patients8; confirmation that A, AB, and B blood types associated with COVID-19 positivity	Evidence of racial and ethnic differences in COVID-19 positivity rates; blood types are associated with COVID-19 risk
GWAS and downstream analysis	GWAS of the main COVID-19 outcomes	New genetic loci to suggest further investigation on these candidate genes⁸	New genetic loci used by other working groups/external collaborations; workgroup combined with other workgroups to explore racial/ethnic differences in COVID-19 positivity rates
COVID-19– Related Phenome-Wide Association Study	Develop a resource to understand genetic variants associated with susceptibility to or outcomes of COVID-19 infection	Using MVP and COVID-19 Host Genetics Initiative9 data: identified traits that share genetic variants associated with severe COVID-19; most COVID-19 severity variants associated with risk factors or COVID-19 complications, such as venous embolism and thrombosis; subgroup of variants was inversely associated with psoriasis and inflammatory lung conditions; variant linked with severe COVID-19 was associated with neutropenia among veterans of African ancestry; older age, higher body mass index, male patients, and patients with a history of respiratory, kidney, bacterial, or metabolic comorbidities experienced greater COVID-19 severity	COVID-19 severity variants associated with risk factors or complications of COVID-19, like venous embolism and thrombosis; multiple genetic variants linked with both COVID-19 severity and other conditions such as circulatory issues, inflammatory conditions, and neutropenia; future studies needed to investigate the underlying mechanisms associated with these phenotype clusters and COVID-19

Abbreviations: AKI, acute kidney injury; APOL1, apolipoprotein L1; GWAS, Genome-Wide Association Study; IFN, interferon; IFNAR2, interferon a/ß receptor 2; IL10RB, interleukin 10 receptor ß subunit; MVP, Million Veteran Program; PRS, Polygenic Risk Scores; SCT, sickle cell trait; VTE, venous thromboembolism.