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

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

JOURNAL=Frontiers in Medicine

VOLUME=8

YEAR=2021

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2021.668024

DOI=10.3389/fmed.2021.668024

ISSN=2296-858X

ABSTRACT=<p><bold>Background:</bold> 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 <italic>MUC5B</italic> 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 <italic>MUC5B</italic> rs35705950 associates with severe COVID-19.</p><p><bold>Methods:</bold> 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 (<italic>n</italic> = 436, 57% male, median age 70 years, 27% died), for replication data from the severe COVID-19 GWAS group from Italy (<italic>n</italic> = 835) and Spain (<italic>n</italic> = 775) was used, each with a control cohort (<italic>n</italic> = 356,735, <italic>n</italic> = 1,255, <italic>n</italic> = 950, respectively). <italic>MUC5B</italic> association analysis was performed including adjustment for age and sex.</p><p><bold>Results:</bold> The rs35705950 T-allele frequency was significantly lower in Dutch white patients (<italic>n</italic> = 83) than in controls (0.04 vs. 0.10; <italic>p</italic> = 0.02). This was validated in the UK biobank cohort (0.08 vs. 0.11; <italic>p</italic> = 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 (<italic>p</italic> = 0.04), and Spanish (<italic>p</italic> = 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); <italic>p</italic> = 6.63 × 10<sup>−6</sup>).</p><p><bold>Conclusions:</bold> This study shows that carriage of the T-allele of <italic>MUC5B</italic> 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.</p>