The CCR5-delta32 variant might explain part of the association between COVID-19 and the chemokine-receptor gene cluster

  1. Juan Gómez
  2. Elías Cuesta-Llavona
  3. Guillermo M. Albaiceta
  4. Marta García-Clemente
  5. Carlos López-Larrea
  6. Laura Amado-Rodríguez
  7. Inés López-Alonso
  8. Tamara Hermida
  9. Ana I. EnrÍquez
  10. Helena Gil
  11. Belén Alonso
  12. Sara Iglesias
  13. Beatriz Suarez-Alvarez
  14. Victoria Alvarez
  15. Eliecer Coto

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Abstract

A polymorphism in the LZTFL1 gene located in the chemokine-receptor gene cluster (chromosome 3p) has been associated with the risk of developing COVID-19. The chemokine receptor-5 (CCR5) maps to this region, and the common 32 bp deletion variant (Δ32) has been associated with the extent of inflammatory disease and the outcome in several viral diseases. Several studies have also suggested that the pharmacological targeting of CCR5 could reduce the impact of SARS-CoV-2 infection and the severity of COVID-19. We sought to investigate whether this polymorphism was associated with the risk of moderate-severe COVID-19.

We genotyped 294 patients who required hospitalization due to COVID-19 (85 were severe cases) and 460 controls. We found a significantly lower frequency of CCR5-Δ32 among the COVID-19 patients (0.10 vs 0.18 in controls; p=0.002, OR=0.48, 95%CI=0.29-0.76 ) . The difference was mainly due to the reduced frequency of CCR5-Δ32 carriers in the severe, significantly lower than in the non-severe patients (p=0.036). Of note, we did not find deletion-homozygotes among the patients compared to 1% among controls. We also confirmed the association between a LZTFL1 variant and COVID-19. Our study points to CCR5 as a promising target for treatment of COVID-19, but requires validation in additional large cohorts. In confirmed by others, the genetic analysis of CCR5-variants (such as Δ32) might help to identify patients with a higher susceptibility to severe COVID-19.

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  1. ScreenIT

    SciScore for 10.1101/2020.11.02.20224659: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: The study was approved by the Ethics Committee of Principado de Asturias (Oviedo, Spain), and all the patients or their representatives gave their consent to participate.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    No key resources detected.

    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:
    The main limitation of our study was the reduced size of the patient′s cohort. However, our results were in agreement with the reported association between chromosome 3p21.31 variants and COVID-19. In this way, the association between CCR5-Δ32 and COVID-19 seems plausible and deserves further validation in larger cohorts. If confirmed, the CCR5 variants might serve as valuable markers to identify individuals predisposed to severe COVID-19. A limitation was also that we did not provide a functional link between the CCR5 deletion and COVID-19 outcomes, and we cannot conclude whether this variant was associated with an overall resistance to SARS-Cov-2 infection or a reduced inflammatory response, or both. Although the CCR5 has not a recognised role in SARS-CoV-2 binding to the host cell, a preliminary study showed that the CCR5 inhibitor Maraviroc was able to decrease the extent of viral-cell fusion and the viral load (Risner et al. 2020). To determine whether CCR5 has a direct role in SARS-CoV-2 infection studies with mice expressing the human viral receptor (ACE-2) and lacking ccr5 should be of upmost relevance (Winckler et al., 2020; Israelow et al., 2020). Finally, the pharmacological blockade of CCR5 has been associated with an improvement of the symptoms in a group of severe COVID-19 patients. In a limited study involving 10 patients the anti-CCR5 antibody Leronlimab showed an improvement of disease symptoms, with a rapid reduction of plasma IL-6 and restoration of the CD4...

    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.

    About SciScore

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  2. Version published to 10.1101/2020.11.02.20224659v1 on medRxiv