Host HLA Allelic Variation Shapes Risk of Severe SARS-CoV-2 Infection and Long COVID 2310004

Abstract Introduction We investigated the relationship between imputed human leukocyte antigen (HLA) alleles to COVID-19 clinical severity within the NIH funded All of Us dataset, which integrates electronic health records and genomic sequences of enrolled participants. Methods The base population was defined as any participant who had been administered a SARS-CoV-2 test and provided genomic sequencing data (n = 113,015). Cohorts were refined by COVID-19 conditions: (1) a positive COVID-19 test (n = 20,872), (2) a negative COVID-19 test (n = 88,680), (3) both a positive test and an ICD-10 diagnosis code for pneumonia due to COVID-19 or lower respiratory infection caused by SARS-CoV-2 (n = 1,079), (4) a positive test and a diagnosis code for Long COVID (n = 509), and (5) ONLY and at least 3 positive COVID-19 tests (n = 1,298), and (6) ONLY and at least 3 negative COVID-19 tests (n = 4,884). HLA Class I and Class II allele imputation utilized a global diversity reference panel utilizing the HIBAG “R” package with a median posterior probability rate greater than 92.7% for the 6 HLA alleles. Results Through this approach, we found several alleles significantly associated with protection from and increased risk of severe COVID-19 infection. Conclusion Our findings expand the limited clinical research on the role of HLA haplotypes in the response to SARS-CoV-2, underscoring the usefulness of large, multi-ancestral clinical and molecular datasets in generating testable hypotheses that have potentially significant clinical applications Funding Source NCATS T32, grant number 1T32TR004767-0 and LA CaTS, grant number U54 GM104940, LSUHSC Medical Student Research Enhancement Program Topic Categories Translational and Interventional Immunology (TI)