Interleukin-6 receptor genetic variation and tocilizumab treatment response to COVID-19

  1. Ammar Ali Almarzooq

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Abstract

Interleukin-6 receptor (IL6R) stimulates the inflammatory pathways as part of the acute-phase response to infection. Tocilizumab is a monoclonal antibody that inhibits both membrane-bound and soluble IL6R and is used to treat inflammatory conditions, including COVID-19. Despite the disproportionate incidence of COVID-19 among underserved, racial, and ethnic minority populations, the efficacy of tocilizumab in hospitalized COVID-19 patients from these populations is unclear. In this work, three genetic markers for the IL6R gene were analyzed across diverse ethnic backgrounds to identify population differences in response to tocilizumab treatment. Genetic structure analyses showed that African populations were significantly different from other described populations. In addition, mapped frequencies of these alleles showed that Sub-Saharan African populations were 3.4x more likely to show an impaired response to tocilizumab than East Asian populations, and 1.8x more likely than European ancestry populations. Existing IL6R genotype results may identify populations at increased therapeutic failure risk. As results from current clinical trials on the efficacy of tocilizumab treatment for extreme COVID-19 infections are conflicting, more studies are needed across diverse patient backgrounds to better understand the genetic factors necessary to predict treatment efficacy. This work demonstrates how pharmacogenomics studies can elucidate genetic variation on treatment efficacy on COVID-19.

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  1. ScreenIT

    SciScore for 10.1101/2021.04.24.21256047: (What is this?)

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

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Population structure analyses: Population structure was examined using Wright’s Fixation Index (FST) for pairwise distances between populations based on three SNPs across IL6R to identify the ancestral relatedness across 26 global populations from the 1000 Genomes Project Phase III (1kG-p3) dataset [34]
    1000 Genomes Project
    suggested: (1000 Genomes Project and AWS, RRID:SCR_008801)
    Divergences were visualized by multidimensional scaling analysis (MDS) using the metaMDS function in the vegan R package [37] and with a hierarchical clustering based on FST values using the hclust function in base R.
    vegan
    suggested: (vegan, RRID:SCR_011950)
    hclust
    suggested: (HCLUST, RRID:SCR_009154)
    These were implemented with the HWChisq function in HardyWeinberg R package [35.
    HardyWeinberg
    suggested: None
    This biogeographic grouping system meets a key need in pharmacogenetics research by enabling consistent communication of the scale of variability in global allele frequencies and is now used by PharmGKB and CPIC [38].
    PharmGKB
    suggested: (PharmGKB, RRID:SCR_002689)

    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: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    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.

    About SciScore

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  2. Version published to 10.1101/2021.04.24.21256047v1 on medRxiv