Proteomic Profiling in Biracial Cohorts Implicates DC-SIGN as a Mediator of Genetic Risk in COVID-19

  1. Daniel H. Katz
  2. Usman A. Tahir
  3. Debby Ngo
  4. Mark Benson
  5. Alexander G. Bick
  6. Akhil Pampana
  7. Yan Gao
  8. Michelle J. Keyes
  9. Adolfo Correa
  10. Sumita Sinha
  11. Dongxiao Shen
  12. Qiong Yang
  13. Jeremy M. Robbins
  14. Zsu-Zsu Chen
  15. Daniel E. Cruz
  16. Bennet Peterson
  17. Pradeep Natarajan
  18. Ramachandran S. Vasan
  19. J. Gustav Smith
  20. Thomas J. Wang
  21. James G. Wilson
  22. Robert E. Gerszten

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Abstract

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by race, though the relative contributions of structural/social and genetic factors remain unclear. 1,2 Very recent unpublished work has identified two genetic risk loci that confer greater risk for respiratory failure in COVID-19: the ABO locus and the 3p21.31 locus. 3 To understand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.

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    SciScore for 10.1101/2020.06.09.20125690: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIRB: Study Approval: 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.
    Consent: Study Approval: 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.
    RandomizationBatches 2 and 3 were a randomly selected sample of the remaining JHS participants.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    25 Proteomic measurements were performed using SOMAscan™, a single-stranded DNA aptamer-based proteomics platform, which contained 1,305 aptamers.
    SOMAscan™
    suggested: None
    All assays in all cohorts were performed using SOMAscan™ reagents according to the manufacturer’s detailed protocol.30 Genotyping and Imputation: Whole genome sequencing (WGS) in JHS has been described previously.
    WGS
    suggested: None
    Genotypes were called using Chiamo (http://www.stats.ox.ac.uk/~marchini/software/gwas/chiamo.html).
    Chiamo
    suggested: (CHIAMO, RRID:SCR_009150)
    We used the 1000 Genomes Phase I version 3 (August 2012) reference panel to perform imputation using a hidden Markov model implemented in MaCH (version 1.0.16)33 for all SNPs passing the following criteria: call rate ≥ 97%, pHWE ≥ 1 × 10−6, Mishap P ≥ 1 × 10−9, Mendel errors ≤ 100, and MAF ≥ 1%.
    MaCH
    suggested: (MACH, RRID:SCR_009621)
    Genotypes were called using Illumina GenomeStudio and imputation performed to the same 1000 Genomes version as for FHS using IMPUTE (v2) for SNPs passing the following criteria: call rate ≥ 95%, pHWE ≥ 1 × 10−6, minor allele frequency ≥ 0.01.
    GenomeStudio
    suggested: (GenomeStudio, RRID:SCR_010973)
    1000 Genomes
    suggested: (1000 Genomes Project and AWS, RRID:SCR_008801)
    IMPUTE
    suggested: (IMPUTE, RRID:SCR_009245)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Limitations: Our study has several important limitations. We have not studied the relationship between these proteins and genes in COVID-19 cases, thus confirming their role in pathogenesis requires further study. While the proteomic profiling discussed here is extensive, it does not cover the entire proteome, and important protein associations may be missed as a result. Further, while changes in aptamer binding are typically reflective of protein levels, it may be the case that ABO-mediated glycosylation alters aptamer binding, thus changing the measurement of the protein without a true change in protein levels. Nonetheless, our data demonstrate that ABO affects the identified proteins, motivating further investigation. Additionally, in the case of DC-SIGN (and CXCL16), we and others have found that variants at the cognate gene are associated with levels of the protein as measured by the aptamer (Supplementary Table 1). Finally, we acknowledge we do not observe an association between the lead risk SNP at 3p21.31 identified by Ellinghaus et al. and CXCL16. Formal colocalization in larger cohorts will be useful in clarifying the gene-protein relationships.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

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  2. Version published to 10.1101/2020.06.09.20125690v1 on medRxiv