The MUC5B Promoter Polymorphism Associates With Severe COVID-19 in the European Population

  1. Coline H. M. van Moorsel
  2. Joanne J. van der Vis
  3. Anna Duckworth
  4. Chris J. Scotton
  5. Claudia Benschop
  6. David Ellinghaus
  7. Henk J. T. Ruven
  8. Marian J. R. Quanjel
  9. Jan C. Grutters

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Abstract

Background: Diversity in response on exposure to severe acute respiratory syndrome coronavirus 2 may be related to the innate immune response in the elderly. The mucin MUC5B is an important component of the innate immune response and expression levels are associated with the MUC5B promoter polymorphism, rs35705950. The high expressing T-allele is a risk allele for the non-infectious aging lung disease idiopathic pulmonary fibrosis (IPF). We investigated if MUC5B rs35705950 associates with severe COVID-19.

Methods: In this retrospective candidate gene case-control study we recruited 108 Dutch patients (69% male, median age 66 years, 77% white) requiring hospitalization for COVID-19 (22% ICU stay, 24% died). For validation, genotypes were obtained from the UK-Biobank ( n = 436, 57% male, median age 70 years, 27% died), for replication data from the severe COVID-19 GWAS group from Italy ( n = 835) and Spain ( n = 775) was used, each with a control cohort ( n = 356,735, n = 1,255, n = 950, respectively). MUC5B association analysis was performed including adjustment for age and sex.

Results: The rs35705950 T-allele frequency was significantly lower in Dutch white patients ( n = 83) than in controls (0.04 vs. 0.10; p = 0.02). This was validated in the UK biobank cohort (0.08 vs. 0.11; p = 0.001). While age and sex differed significantly between cases and control, comparable results were obtained with age and sex as confounding variables in a multivariate analysis. The association was replicated in the Italian ( p = 0.04), and Spanish ( p = 0.03) case-control cohorts. Meta-analysis showed a negative association for the T-allele with COVID-19 (OR = 0.75 (CI: 0.67–0.85); p = 6.63 × 10 −6 ).

Conclusions: This study shows that carriage of the T-allele of MUC5B rs35705950 confers protection from development of severe COVID-19. Because the T-allele is a known risk allele for IPF, this study provides further evidence for the existence of trade-offs between optimal mucin expression levels in the aging lung.

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  1. Version published to 10.3389/fmed.2021.668024
  2. ScreenIT

    SciScore for 10.1101/2020.05.12.20099333: (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 Medical research Ethics Committees United (MEC-U) of St. Antonius Hospital and all patients provided written informed consent (approval number R05-08A).
    Consent: The study was approved by The Medical research Ethics Committees United (MEC-U) of St. Antonius Hospital and all patients provided written informed consent (approval number R05-08A).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Statistical analysis: SPSS 24 (IBM, Armonk, New York, USA) was used for statistical analysis.
    SPSS
    suggested: (SPSS, RRID:SCR_002865)

    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:
    Although the finding is of interest it must be noted that the small sample size and the lack of replication is a major limitation of the current study. Furthermore, due to limited sample size we were not able to perform an association analysis in non-white subjects, while they suffer disproportionally from COVID-19. In conclusion, we found that the T-allele of MUC5B rs35705950 confers protection from development of severe COVID-19 disease. Because the T-allele is a known risk allele for pulmonary fibrosis, the study provides further evidence for the existence of trade-offs between optimal expression levels in the aging lung. Further studies with lager sample size are needed to understand the importance of our finding.

    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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  3. Version published to 10.1101/2020.05.12.20099333v1 on medRxiv