Viral infections including Human immunodeficiency virus (HIV), hepatitis C virus (HCV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have placed a substantial strain on human health and the health care system. These infections have specifically had broad impacts on veteran health in the US. Host factors influence how humans respond to infectious agents and develop adverse health outcomes after infection. Although previous genome-wide association studies (GWAS) have identified loci associated with susceptibility and progression for several infections, understanding the role of host genetic and epigenetic factors on chronic disease comorbidities, aging, and long-term outcomes in the setting of viral infections has been hampered by sample size, heterogeneous populations, and discordant measurements/definitions of key phenotypes. Recent epigenome-wide association studies (EWAS) have uncovered DNA methylation markers associated with noncommunicable diseases (NCDs, such as coronary heart disease, diabetes, heart failure, chronic kidney disease), as well as HIV infection. However, the epigenetic predictors for incident NCDs and mortality are largely unknown among people with viral infections. Viral infections (e.g., HIV) can have a substantial impact on epigenetics, which may affect long-term health outcomes. Additionally, acceleration of the epigenetic clock or age has emerged as a novel biomarker of biological aging and can predict disease outcomes and mortality. Therefore, we will systematically investigate genetic and epigenetic predictors of NCDs and mortality in the following Aims. 1) To identify genetic and epigenetic predictors of age-related morbidity and mortality as well as modification effect of HIV infection among multi-ethnic veterans; 2) To identify genetic and epigenetic factors associated with morbidity and mortality among multi- ethnic veterans with HCV infection; 3) To identify genetic and epigenetic factors of long-term comorbidities, accelerated aging and mortality, as well as mediation effect of COVID-19 among multi-ethnic veterans. Impact: Viral infections including HIV, HCV and SARS-CoV-2 broadly affects veteran’s health and reduces the quality of life (healthspan) and life expectancy (lifespan) through a range of comorbidities. The molecular mechanisms underlying the morbidity and mortality after viral infections of HIV, HCV and SARS-CoV-2 are largely unknown. The proposed genetic and epigenetic study can reveal the genetic and epigenetic factors linking viral infection (acute, chronic, and resolved) and major NCD outcomes and mortality among multi-ethnic veterans, shed lights on potential targets for new prevention and intervention, provide insights into the comorbidity and aging process for all people, and develop systematic and precision medicine strategies to improve veteran’s health.

Viral infections including human immunodeficiency virus (HIV), hepatitis C virus (HCV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have placed a substantial strain on the health care system and have broad impacts on the health of US veterans. Due to the influence host factors have on outcomes post- infection, we will assess the impact of genetic and epigenetic factors on comorbidities and long-term outcomes among people with viral infection (acute, chronic, and resolved). Using the massive sample size, centralized electronic health records, and multi-ethnic population from the Million Veteran Program (MVP), we will employ advanced analytical approaches to identify genetic and epigenetic markers and molecular systems underlying the susceptibility, progression, and outcomes of HIV, HCV and SARS-CoV-2 infection. These results will provide substantial insight into the impact of infectious diseases on the health and lifespan of veterans with viral infections, improving diagnostic and therapeutic approaches to multi-morbidity and the aging process.