The MUC5B Promotor Polymorphism Associates with Severe COVID-19 in the European Population (preprint)

Diversity in response on exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is common and 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). However, given the theory of trade-offs in aging lung disease and the importance of mucin expression for an adequate immune response, we hypothesized that the T-allele is protective against COVID-19 disease.Methods: MUC5B rs35705950 was genotyped for 108 Dutch patients requiring hospitalisation for COVID-19 at St Antonius Hospital. For replication, genotypes were obtained from the severe COVID-19 GWAS group for Italian (n=835) and Spanish (n=775) patients, and from the UK Biobank (n= 436 patients), each with respective control cohorts.Results: The minor T-allele frequency of rs35705950 was significantly lower in Dutch white patients (n=83) than in controls (0.04 vs 0.10; p=0.02). This finding was replicated in the Italian (0.10 vs 0.13; p=0.04), the Spanish (0.10 vs 0.13; p=0.03), and the UK (0.08 vs 0.11; p=0.001) white case-control cohorts. Meta-analysis showed a significant negative association for the T-allele with COVID-19 disease (0.75 (CI: 0.67–0.85); p=6.63e-06).Conclusions: The MUC5B rs35705950 promoter polymorphism associates with COVID-19. The risk allele (T) for IPF is protective against development of severe COVID-19. This is a further example of a trade-off in aging lung diseases.Funding: This study was funded by ZonMW TopZorg St Antonius Care grant nr 842002001; ZonMW Topspecialistische Zorg en Onderzoek grant nr 10070012010004; Nederlandse Vereniging van Artsen voor Longziekten en Tuberculose COVID-19 grant; GW4 BioMed Medical Research Council Doctoral Training Partnership. Conflict of Interest: All authors declare no competing interests.Ethical Approval: 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).

THE MUC5B PROMOTOR POLYMORPHISM ASSOCIATES WITH SEVERE COVID-19 (preprint)

Background Diversity in response to exposition to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is common and may be related to the innate immune response. 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 of rs35705950 is an accepted risk allele for a non-infectious aging lung disease called idiopathic pulmonary fibrosis (IPF). However, given the theory of trade-offs in aging lung disease and the importance of high expression for an adequate immune response, we hypothesize that the T-allele is protective against severe coronavirus disease 2019 (COVID-19). Methods We collected demographics, radiology, survival data and MUC5B rs35705950 allele status for 108 patients requiring hospitalisation for COVID-19 at St Antonius Hospital in The Netherlands. For comparison of allele frequencies and allele carriership with a white control cohort, the patient cohort was divided in a white (n=83) and non-white cohort. Results The patients had a median age of 66 years and consisted predominantly of males (74%) and 23 patients (21%) died. The T-allele frequencies of rs35705950 in white patients was 0.04 which was significantly lower than the T-allele frequency of 0.10 in white controls (p= 0.02). Moreover, comparison of the number of carriers and non-carriers of the T allele showed that only 8.4% of patients carried the T-allele versus 18% of controls (p=0.029; OR= 0.41, CI=0.19-0.94). Conclusions The MUC5B rs35705950 promoter polymorphism associates with COVID-19. The risk allele (T) for IPF is protective against the development of severe COVID-19 disease. This is a further example of a trade-off between optimal expression levels in the respiratory system which associates with aging diseases. However, these results require further investigation.