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

Coline H M van Moorsel; Joanne J van der Vis; Anna Duckworth; Chris J Scotton; Claudia Benschop; David Ellinghaus; Henk J T Ruven; Marian J R Quanjel; Jan C Grutters

doi:10.3389/fmed.2021.668024

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

Front Med (Lausanne). 2021 Nov 23:8:668024. doi: 10.3389/fmed.2021.668024. eCollection 2021.

Authors

Coline H M van Moorsel^{1

2}, Joanne J van der Vis^{1

3}, Anna Duckworth⁴, Chris J Scotton⁴, Claudia Benschop^{1

5}, David Ellinghaus^{6

7}, Henk J T Ruven³, Marian J R Quanjel¹, Jan C Grutters^{1

2}

Affiliations

¹ Department of Pulmonology, St Antonius ILD Center of Excellence, St. Antonius Hospital, Nieuwegein, Netherlands.
² Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, Netherlands.
³ Department of Clinical Chemistry, St Antonius ILD Center of Excellence, St. Antonius Hospital, Nieuwegein, Netherlands.
⁴ College of Medicine & Health, Institute of Biomedical & Clinical Science, University of Exeter, Exeter, United Kingdom.
⁵ Department of Medical Microbiology and Immunology, St Antonius ILD Center of Excellence, St. Antonius Hospital, Nieuwegein, Netherlands.
⁶ Genetics and Bioinformatics Group, Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.
⁷ Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Protein Research, Disease Systems Biology, University of Copenhagen, Copenhagen, Denmark.

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.

Keywords: COVID-19; MUC5B; SARS-CoV-2; aging lung; idiopathic pulmonary fibrosis; innate immunity; mucus.