THE <i>MUC5B</i> PROMOTOR POLYMORPHISM ASSOCIATES WITH SEVERE COVID-19

Moorsel, Coline H.M. van; Vis, Joanne J. van der; Benschop, Claudia; Ruven, Henk J.T.; Quanjel, Marian J.R.; Grutters, Jan C.

doi:10.1101/2020.05.12.20099333

Cited by 8 publications

(8 citation statements)

References 28 publications

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“…It is intriguing that the most strongly associated IPF variant [ 9 , 11 ], rs35705950 at the MUC5B gene locus, which its risk allele (T) associated with a five-fold increase in IPF risk [9] , is negatively associated with COVID-19 regardless of severity, suggesting that this IPF risk allele may protect against COVID-19. This association has been reported in a small study [30] , and a protective role for MUC5B in airway defense has been described [31] . The IPF risk allele (T) of the rs35705950 is associated with increased MUC5B expression in lung tissue [13] , which has been associated with muco-ciliary dysfunction and increased bleomycin-induced fibrosis in mice [32] .…”

Section: Discussionsupporting

confidence: 57%

Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity

et al. 2021

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Background Idiopathic pulmonary fibrosis (IPF) is a complex lung disease, characterized by progressive lung scarring. Severe COVID-19 is associated with substantial pneumonitis and has a number of shared major risk factors with IPF. This study aimed to determine the genetic correlation between IPF and severe COVID-19 and assess a potential causal role of genetically increased risk of IPF on COVID-19 severity. Methods The genetic correlation between IPF and COVID-19 severity was estimated with linkage disequilibrium (LD) score regression. We performed a Mendelian randomization (MR) study for IPF causality in COVID-19. Genetic variants associated with IPF susceptibility ( P <5 × 10 −8 ) in previous genome-wide association studies (GWAS) were used as instrumental variables (IVs). Effect estimates of those IVs on COVID-19 severity were gathered from the GWAS meta-analysis by the COVID-19 Host Genetics Initiative (4,336 cases & 623,902 controls). Findings We detected a positive genetic correlation of IPF with COVID-19 severity (rg=0·31 [95% CI 0·04–0·57], P = 0·023). The MR estimates for severe COVID-19 did not reveal any genetic association (OR 1·05, [95% CI 0·92–1·20], P = 0·43). However, outlier analysis revealed that the IPF risk allele rs35705950 at MUC5B had a different effect compared with the other variants. When rs35705950 was excluded, MR results provided evidence that genetically increased risk of IPF has a causal effect on COVID-19 severity (OR 1·21, [95% CI 1·06–1·38], P = 4·24 × 10 −3 ). Furthermore, the IPF risk-allele at MUC5B showed an apparent protective effect against COVID-19 hospitalization only in older adults (OR 0·86, [95% CI 0·73–1·00], P = 2·99 × 10 −2 ) . Interpretation The strongest genetic determinant of IPF, rs35705950 at MUC5B , seems to confer protection against COVID-19, whereas the combined effect of all other IPF risk loci seem to confer risk of COVID-19 severity. The observed effect of rs35705950 could either be due to protective effects of mucin over-production on the airways or a consequence of selection bias due to (1) a patient group that is heavily enriched for the rs35705950 T undertaking strict self-isolation and/or (2) due to survival bias of the rs35705950 non-IPF risk allele carriers. Due to the diverse impact of IPF causal variants on SARS-CoV-2 infection, with a possible selection bias as an explanation, further investigation is needed to address this apparent paradox between variance at MUC5B and other IPF genetic risk factors. Funding Novo Nordisk Foundation and Oak Foundation.

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Section: Discussionsupporting

confidence: 57%

Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity

et al. 2021

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“…However, a recent study indicated the presence of elevated levels of secreted MUC1 and MUC5AC in the sputum aspirated from the trachea of COVID-19 patients ( 62 ). COVID-19 patients also have a lower allelic frequency of the MUC5B genetic variant rs35705950 than healthy controls, which is associated with a higher level of expression of MUC5B, suggesting a protective role for MUC5B ( 63 ). The role of soluble and transmembrane mucins and their glycans during COVID-19 pathogenicity needs to be addressed to fully understand the course of the disease ( Fig.…”

Section: Mucosal Defense Against Sars-cov-2mentioning

confidence: 99%

Defensive Properties of Mucin Glycoproteins during Respiratory Infections—Relevance for SARS-CoV-2

Chatterjee

Putten

Strijbis

2020

mBio

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Mucus plays a pivotal role in protecting the respiratory tract against microbial infections. It acts as a primary contact site to entrap microbes and facilitates their removal from the respiratory tract via the coordinated beating of motile cilia. The major components of airway mucus are heavily O-glycosylated mucin glycoproteins, divided into gel-forming mucins and transmembrane mucins. The gel-forming mucins MUC5AC and MUC5B are the primary structural components of airway mucus, and they enable efficient clearance of pathogens by mucociliary clearance. MUC5B is constitutively expressed in the healthy airway, whereas MUC5AC is upregulated in response to inflammatory challenge. MUC1, MUC4, and MUC16 are the three major transmembrane mucins of the respiratory tracts which prevent microbial invasion, can act as releasable decoy receptors, and activate intracellular signal transduction pathways. Pathogens have evolved virulence factors such as adhesins that facilitate interaction with specific mucins and mucin glycans, for example, terminal sialic acids. Mucin expression and glycosylation are dependent on the inflammatory state of the respiratory tract and are directly regulated by proinflammatory cytokines and microbial ligands. Gender and age also impact mucin glycosylation and expression through the female sex hormone estradiol and age-related downregulation of mucin production. Here, we discuss what is currently known about the role of respiratory mucins and their glycans during bacterial and viral infections of the airways and their relevance for the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Understanding the impact of microbe-mucin interaction in the respiratory tract could inspire the development of novel therapies to boost mucosal defense and combat respiratory infections.

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“…The allele rs35705950*T, a risk factor for IPF, was associated with protection against the development of severe COVID-19 in older adults ( Fadista et al, 2021 ). The observed association with rs35705950 could be due to a protective effect of high mucin production in the airways, but the authors could not rule out a patient selection bias associated with the rs35705950 SNP ( van Moorsel et al, 2020 ) Other mucin family members might also be candidates for studies of COVID-19 complications in the gut and airways.…”

Section: Host Genetics Beyond Hla and Kirmentioning

confidence: 99%

An immunogenetic view of COVID-19

et al. 2021

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Meeting the challenges brought by the COVID-19 pandemic requires an interdisciplinary approach. In this context, integrating knowledge of immune function with an understanding of how genetic variation influences the nature of immunity is a key challenge. Immunogenetics can help explain the heterogeneity of susceptibility and protection to the viral infection and disease progression. Here, we review the knowledge developed so far, discussing fundamental genes for triggering the innate and adaptive immune responses associated with a viral infection, especially with the SARS-CoV-2 mechanisms. We emphasize the role of the HLA and KIR genes, discussing what has been uncovered about their role in COVID-19 and addressing methodological challenges of studying these genes. Finally, we comment on questions that arise when studying admixed populations, highlighting the case of Brazil. We argue that the interplay between immunology and an understanding of genetic associations can provide an important contribution to our knowledge of COVID-19.

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THE MUC5B PROMOTOR POLYMORPHISM ASSOCIATES WITH SEVERE COVID-19

Cited by 8 publications

References 28 publications

Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity

Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity

Defensive Properties of Mucin Glycoproteins during Respiratory Infections—Relevance for SARS-CoV-2

An immunogenetic view of COVID-19

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