483 Human leukocyte antigen (HLA) alleles associated with severe COVID-19 outcomes in the All of Us cohort

Objectives/Goals: The primary objective of this study is to investigate the relationship between human leukocyte antigen (HLA) alleles to COVID-19 clinical severity, specifically: hospitalization, mortality, pneumonia by COVID-19, post-acute sequelae of SARS-CoV-2 infection (PASC), and clinical lab values. Methods/Study Population: We are conducting a retrospective cohort study utilizing the All of Us controlled tier dataset. The base population was defined as any patients with a COVID-19 diagnosis code (ICD-10: U07.1 or SNOMED: 840539006) and genomic sequencing data. PASC definitions were developed by the N3C consortium and refined in house. A total of 15,252 patients (64.5% female; 50.4% self-reported European ancestry; 18.8% self-reported African ancestry; 34.5% > 65 years old) are included in this study. HLA Class I and Class II alleles will be imputed from a global diversity reference panel utilizing the HIBAG “R” package. Results/Anticipated Results: Controlling for age, sex, race, and COVID-19 vaccination status, we anticipate determining the HLA alleles associated with severe clinical outcomes, such as Pneumonia by COVID (n = 1,436) and PASC (ICD-10:U09.9 or SNOMED:119303003 or OMOP:OMOP5160861 [n = 498]). We will assess which HLA alleles are associated with markedly different IgM and IgG COVID-19 serum antibody levels (n = 1,024). Coexisting conditions, i.e., type 2 diabetes, chronic obstructive pulmonary disease, and hypertension, will be controlled for with the Charlson comorbidity index. The accuracy of HLA allelic imputation will be validated in patients with long-read whole genome sequences. Discussion/Significance of Impact: Our findings can help identify patients who may be at risk of severe COVID-19 infection, particularly those undergoing bone marrow or organ transplantation. We hope this study will accelerate personalized care of COVID-19 in vulnerable populations.