Ancestral origins are associated with SARS-CoV-2 susceptibility and protection in a Florida patient population

PLOS ONE RESEARCH ARTICLE Ancestral origins are associated with SARSCoV-2 susceptibility and protection in a Florida patient population Yiran Shen ID1, Bhuwan Khatri ID2, Santosh Rananaware ID3, Danmeng Li ID4, David A. Ostrov4, Piyush K. Jain ID3, Christopher J. Lessard ID2, Cuong Q. Nguyen ID1,5,6* a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 1 Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, Florida, United States of America, 2 Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America, 3 Department of Chemical Engineering, University of Florida, Gainesville, Florida, United States of America, 4 Department of Pathology, Immunology & Laboratory Medicine, University of Florida, Gainesville, Florida, United States of America, 5 Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, Florida, United States of America, 6 Center of Orphaned Autoimmune Diseases, University of Florida, Gainesville, Florida, United States of America * OPEN ACCESS Citation: Shen Y, Khatri B, Rananaware S, Li D, Ostrov DA, Jain PK, et al. (2023) Ancestral origins are associated with SARS-CoV-2 susceptibility and protection in a Florida patient population. PLoS ONE 18(1): e0276700. https://doi.org/10.1371/ journal.pone.0276700 Editor: Agnieszka Rynda-Apple, Montana State University, UNITED STATES Received: April 12, 2022 Accepted: October 11, 2022 Published: January 17, 2023 Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here: https://doi.org/10.1371/journal.pone.0276700 Copyright: © 2023 Shen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: The genotyping data been deposited in NCBI’s Gene Expression Omnibus (GEO) and are accessible through GEO Series accession number GSE211972 (https:// Abstract COVID-19 is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The severity of COVID-19 is highly variable and related to known (e.g., age, obesity, immune deficiency) and unknown risk factors. The widespread clinical symptoms encompass a large group of asymptomatic COVID-19 patients, raising a crucial question regarding genetic susceptibility, e.g., whether individual differences in immunity play a role in patient symptomatology and how much human leukocyte antigen (HLA) contributes to this. To reveal genetic determinants of susceptibility to COVID-19 severity in the population and further explore potential immunerelated factors, we performed a genome-wide association study on 284 confirmed COVID-19 patients (cases) and 95 healthy individuals (controls). We compared cases and controls of European (EUR) ancestry and African American (AFR) ancestry separately. We identified two loci on chromosomes 5q32 and 11p12, which reach the significance threshold of suggestive association (p<1x10-5 threshold adjusted for multiple trait testing) and are associated with the COVID-19 susceptibility in the European ancestry (index rs17448496: odds ratio[OR] = 0.173; 95% confidence interval[CI], 0.08–0.36 for G allele; p = 5.15× 10−5 and index rs768632395: OR = 0.166; 95% CI, 0.07–0.35 for A allele; p = 4.25×10−6, respectively), which were associated with two genes, PPP2R2B at 5q32, and LRRC4C at 11p12, respectively. To explore the linkage between HLA and COVID-19 severity, we applied fine-mapping analysis to dissect the HLA association with mild and severe cases. Using In-silico binding predictions to map the binding of risk/protective HLA to the viral structural proteins, we found the differential presentation of viral peptides in both ancestries. Lastly, extrapolation of the identified HLA from the cohort to the worldwide population revealed notable correlations. The study uncovers possible differences in susceptibility to COVID-19 in different ancestral origins in the genetic background, which may provide new insights into the pathogenesis and clinical treatment of the disease. PLOS ONE | https://doi.org/10.1371/journal.pone.0276700 January 17, 2023 1 / 20 PLOS ONE www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc= GSE211972). Funding: The study is supported financially in part by PHS grants DE028544 and DE028544-02S1 from the National Institute of Dental and Craniofacial Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. The HLA association with COVID-19 Introduction In December 2019, a novel coronavirus, severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), emerged in Wuhan, Hubei Province, China, initiating a breakout of atypical acute respiratory disease, termed coronavirus disease 2019 (COVID-19). SARS-CoV-2 is a betacoronavirus in the family of Coronaviridae; the virus contains four structural proteins: S (spike), E (envelope), M (membrane), and N (nucleocapsid), sixteen non-structural proteins (nsp1−16) and eleven accessory proteins, which support viral essential physiological function and evasion from the host immune system [1]. The complex structure of the virus provides multiple possible targets for antiviral prevention and treatment; however, the lack of comprehensive knowledge of viral infection and host immune response has hampered efforts to predict the disease course and identify effective therapeutic candidates. One of the most striking features of SARS-CoV-2 is consequence variability, ranging from asymptomatic to symptomatic viral pneumonia and finally to life-threatening acute respiratory distress syndrome [2]. A majority of patients recovered during early infection, but a smaller percentage of patients were more likely to progress and eventually die from severe systemic inflammatory response syndrome. Several factors are associated with disease severity, e.g., age, gender, pre-existing conditions [3, 4] and race [5–7]. To reveal the underlying pathogenesis of SARS-CoV-2 susceptibility and disease progression, genome-wide association studies (GWAS) provide additional clues regarding the pathogenesis of complex diseases by identifying potential susceptible allelic variants. Several loci on the different chromosomes have been previously reported to be associated with COVID-19 severity [8–10]. Some studies have focused on the genetic linkage between HLA alleles and SARS-CoV-2 infection. The class I (HLA-A, -B, and -C) and class II HLA (HLA-DR, -DQ, and -DP) exhibit a high de (...truncated)