Simple SummaryThis study analyzed data from the National COVID Cohort Collaborative, the largest US COVID-19 database, to determine if an association exists between COVID-19 and blood levels of high-density lipoprotein, and high-density lipoprotein’s main protein component, apolipoprotein A1. Our findings suggest that individuals with higher levels of high-density lipoprotein and apolipoprotein A1 were less likely to be infected with SARS-CoV-2 and were less likely to develop severe COVID-19 requiring hospitalization or invasive medical interventions. They were also less likely to develop acute kidney injury. On the other hand, the presence of underlying health issues (comorbidities) increased the risk of developing severe COVID-19 and acute kidney injury. African American and Hispanic populations were more likely to experience severe disease, while smoking and being male appeared to reduce the incidence of infection but increased the risk of developing severe disease and acute kidney injury. This study is the first to explore the association of high-density lipoprotein and apolipoprotein A1 with COVID-19 outcomes using US population data.AbstractThis study analyzed data from the National COVID Cohort Collaborative (N3C) database to investigate whether high-density lipoprotein (HDL) and its major protein component, apolipoprotein A1 (apoA1), are associated with severe COVID-19 sequelae, specifically acute kidney injury (AKI) and severe COVID-19 disease as defined by the infection resulting in hospitalization, extracorporeal membrane oxygenation (ECMO), invasive ventilation, or death. Our study included a total of 1,415,302 subjects with HDL values and 3589 subjects with apoA1 values. Higher levels of both HDL and apoA1 were associated with a lower incidence of infection as well as a lower incidence of severe disease. Higher HDL levels were also associated with a lower incidence of developing AKI. Most comorbidities were negatively correlated with SARS-CoV-2 infection, presumably due to the behavioral changes that occurred as a result of the precautions taken by individuals with underlying comorbidities. The presence of comorbidities, however, was associated with developing severe COVID-19 disease and AKI. African American and Hispanic populations experienced worse outcomes, including a higher incidence of infection and the development of severe disease, as well as AKI. Smoking and being male were associated with a lower incidence of infection, while they were risk factors for the development of severe disease and AKI. The results on cholesterol and diabetes drugs warrant further research, given that the database included multiple drugs in each category impeding for analysis of specific medications. Despite the current limitations in the N3C data, this study is the first to investigate the roles of HDL and apoA1 on the outcomes of COVID-19 using the US population data.