Brief Summary
COVID-19 is one of the most consequential pandemics in the last century, yet the biological mechanisms that confer disease risk are incompletely understood. Further, heterogeneity in disease outcomes is influenced by race, though the relative contributions of structural/social and genetic factors remain unclear.1,2 Very recent unpublished work has identified two genetic risk loci that confer greater risk for respiratory failure in COVID-19: the ABO locus and the 3p21.31 locus.3 To understand how these loci might confer risk and whether this differs by race, we utilized proteomic profiling and genetic information from three cohorts including black and white participants to identify proteins influenced by these loci. We observed that variants in the ABO locus are associated with levels of CD209/DC-SIGN, a known binding protein for SARS-CoV and other viruses,4 as well as multiple inflammatory and thrombotic proteins, while the 3p21.31 locus is associated with levels of CXCL16, a known inflammatory chemokine.5 Thus, integration of genetic information and proteomic profiling in biracial cohorts highlights putative mechanisms for genetic risk in COVID-19 disease.
Competing Interest Statement
The authors have declared no competing interest.
Funding Statement
The Jackson Heart Study (JHS) is supported and conducted in collaboration with Jackson State University (HHSN268201800013I), Tougaloo College (HHSN268201800014I), the Mississippi State Department of Health (HHSN268201800015I/HHSN26800001) and the University of Mississippi Medical Center (HHSN268201800010I, HHSN268201800011I and HHSN268201800012I) contracts from the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute for Minority Health and Health Disparities (NIMHD). The Framingham Heart Study (FHS) acknowledges the support of contracts NO1-HC-25195, HHSN268201500001I and 75N92019D00031 from the National Heart, Lung and Blood Institute and grant supplement R01 HL092577-06S1 for this research. Dr. Katz is supported by NHLBI T32 postdoctoral training grant (T32HL007374-40). Dr. Tahir is supported by the Ruth L. Kirchstein post-doctoral individual National Research Award (F32HL150992). Dr. Cruz is supported by the KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst (NIH/NCATS Award TR002542). Dr. Robbins is supported by the John S. LaDue Memorial Fellowship in Cardiology at Harvard Medical School. Dr. Benson is supported by NHLBI K08HL145095 award. J. Gustav Smith was supported by grants from the Swedish Heart-Lung Foundation (2016-0134, 2016-0315 and 2019-0526), the Swedish Research Council (2017-02554), the European Research Council (ERC-STG-2015-679242), the Crafoord Foundation, Skane University Hospital, the Scania county, governmental funding of clinical research within the Swedish National Health Service, a generous donation from the Knut and Alice Wallenberg foundation to the Wallenberg Center for Molecular Medicine in Lund, and funding from the Swedish Research Council (Linnaeus grant Dnr 349-2006-237, Strategic Research Area Exodiab Dnr 2009-1039) and Swedish Foundation for Strategic Research (Dnr IRC15-0067) to the Lund University Diabetes Center. Drs. Gerszten, Wang and Wilson are supported by NIH R01 DK081572. Drs. Gerszten, Wang, and Ramachandran are supported by NIH R01 HL132320. Molecular data for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). Genome sequencing for NHLBI TOPMed: The Jackson Heart Study (phs000964.v1.p1) was performed at the Northwest Genomics Center (HHSN268201100037C). Core support including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Core support including phenotype harmonization, data management, sample-identity QC, and general program coordination were provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract HHSN268201800001I). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed.
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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
The human study protocols were approved by the Institutional Review Boards of Beth Israel Deaconess Medical Center, Boston University Medical Center, Lund University, and University of Mississippi Medical Center, and all participants provided written informed consent.
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Paper in collection COVID-19 SARS-CoV-2 preprints from medRxiv and bioRxiv
The Chan Zuckerberg Initiative, Cold Spring Harbor Laboratory, the Sergey Brin Family Foundation, California Institute of Technology, Centre National de la Recherche Scientifique, Fred Hutchinson Cancer Center, Imperial College London, Massachusetts Institute of Technology, Stanford University, University of Washington, and Vrije Universiteit Amsterdam.
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