Minimal observed impact of HLA genotype on hospitalization and severity of SARS‐CoV ‐2 infection

  1. Austin Nguyen
  2. Tasneem Yusufali
  3. Jill A. Hollenbach
  4. Abhinav Nellore
  5. Reid F. Thompson

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Abstract

HLA is a critical component of the viral antigen presentation pathway. We investigated the relationship between the severity of SARS‐CoV‐2 disease and HLA type in 3235 individuals with confirmed SARS‐CoV‐2 infection. We found only the DPB1 locus to be associated with the binary outcome of whether an individual developed any COVID‐19 symptoms. The number of peptides predicted to bind to an HLA allele had no significant relationship with disease severity both when stratifying individuals by ancestry or age and in a pooled analysis. Overall, at the population level, we found HLA type is significantly less predictive of COVID‐19 disease severity than certain demographic factors and clinical comorbidities.

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  1. Version published to 10.1111/tan.14574
  2. ScreenIT

    SciScore for 10.1101/2021.12.22.21268062: (What is this?)

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

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    HLA-peptide predicted binding: We obtained SARS-CoV-2 peptide sequences by k-merizing FASTA protein sequences obtained from the NCBI RefSeq database (NC_045512.2 and NC_004718.3) into 8- to 12-mers.
    RefSeq
    suggested: (RefSeq, RRID:SCR_003496)
    These k-mers were filtered by NetChop v3.1 using default settings with a cutoff of 0.1.
    NetChop
    suggested: None

    Results from OddPub: Thank you for sharing your data.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    We note several limitations to our work. Firstly, the proportion of SARS-CoV-2 peptides that we tested were generated through whole-peptidome in silico analysis of SARS-CoV-2. This may not be representative of the actual SARS-CoV-2 peptides presented in a given individual, whether due to biological sources such as viral variation, or methodological sources such as potential inaccuracies in peptide-MHC binding affinity predictions. Secondly, individuals who suffered debilitating infections may have been less likely to participate in the survey, and no individuals who died of COVID-19 were able to participate in the study, potentially resulting in an undercounting of the most severe phenotypes. Further, the cohort was primarily European, with much smaller sample sizes for African, Asian, and Amerindian ancestry. Lastly, these data were composed entirely of the unvaccinated cohort, as this population was tested and surveyed before the release of the many SARS-CoV-2 vaccines. A number of other studies (15–18,23–25) have examined the relationship between HLA alleles and COVID-19 severity, and few have found alleles significantly associated with severity. In the majority of these studies, the large number of possible alleles in each study reduced the statistical power to identify significant alleles after multiple testing correction. Further, a number of studies reporting statistical significant associations between severity and HLA type were regional; they tended to have more ethn...

    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.

    Results from scite Reference Check: We found no unreliable references.

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  3. Version published to 10.1101/2021.12.22.21268062v1 on medRxiv