Effect of <scp>M</scp>uc5b promoter polymorphism on disease predisposition and survival in idiopathic interstitial pneumonias

Vis, Joanne J. van der; Snetselaar, Reinier; Kazemier, Karin M.; Klooster, Liesbeth ten; Grutters, Jan C.; Moorsel, Coline H.M. van

doi:10.1111/resp.12728

Cited by 60 publications

(51 citation statements)

References 22 publications

(67 reference statements)

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“…IPF is a rare non-infectious pulmonary aging disease of unknown cause characterized by insidious onset of disease in patients without a history of pulmonary infection. Subsequent research showed that the MUC5B T-allele not only predisposes to IPF but to a variety of chronic progressive forms of pulmonary fibrosis [24][25][26][27] . The key cell in the pathogenesis of pulmonary fibrosis is the alveolar type II (AT2) cell.…”

Section: Discussionmentioning

confidence: 99%

THE MUC5B PROMOTOR POLYMORPHISM ASSOCIATES WITH SEVERE COVID-19

Moorsel

Vis

Benschop

et al. 2020

Preprint

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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). MethodsWe 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. ResultsThe 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 Tallele versus 18% of controls (p=0.029; OR= 0.41, CI=0.19-0.94). ConclusionsThe 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.

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Section: Discussionmentioning

confidence: 99%

THE MUC5B PROMOTOR POLYMORPHISM ASSOCIATES WITH SEVERE COVID-19

Moorsel

Vis

Benschop

et al. 2020

Preprint

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“…This association is maintained in all tested populations that had greater than a 1% prevalence of the minor allele including Mexican [84], Chinese [85] and Japanese cohorts [86] but not in a Korean population where the allele frequency was less than 1% [84]. The MUC5B promoter variant is also associated with phenotypic variability in IPF including prevalence of ground glass opacities, subpleural axial distribution of fibrosis, and survival [82,[165][166][167][168][169][170][171]. The MUC5B promoter polymorphism is also associated with increased prevalence of interstitial abnormalities in asymptomatic controls [172] suggesting the utility of rs35705950 in the early detection of IPF.…”

Section: Introductionmentioning

confidence: 99%

Regulation of MUC5B Expression in Idiopathic Pulmonary Fibrosis

Helling

Gerber

Kadiyala

et al. 2017

Am J Respir Cell Mol Biol

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Idiopathic pulmonary fibrosis (IPF) is the most common and the most aggressive fibrosing interstitial lung disease (ILD). Despite recent promising clinical trials, IPF remains incurable and largely untreatable. Genetic studies have identified several risk loci for both sporadic and familial forms of IPF. A single variant upstream of MUC5B is predicted to account for more than 30% of all IPF risk. This variant, rs35705950, is associated with expression of MUC5B in healthy lung tissue. However, the mechanism underlying the relationship between rs35705950 and MUC5B expression remains unclear.The first goal of my thesis research was to determine whether rs35705950 is also a risk factor for other forms of ILD. Genomic DNA from individuals with IPF, HP, COPD, iNSIP, and RB-ILD was obtained and genotyped for the common MUC5B promoter variant. In these populations the risk allele was associated with IPF and iNSIP which suggested a potential shared disease mechanism. Additionally, I showed that in the IPF and control populations rs35705950 is associated with lung MUC5B expression.The second goal of my thesis research was to investigate MUC5B promoter DNA methylation which has previously been shown to play a role in MUC5B expression.Methylation analysis of the 4KB region upstream of MUC5B identified two differentially methylated regions (DMRs) associated with IPF, one DMR associated with MUC5B iv expression, and one DMR associated with rs35705950. The IPF, MUC5B expression, and rs35705950 associated DMRs are all differentially methylated at a cluster of 11 CpG motifs. overlapping DMR, including the motif disrupted by rs35705950. These findings suggest that DNA methylation may play a role in MUC5B gene regulation and IPF risk.Next, I used cross species analysis to identify highly conserved domains within the overlapping DMR. Evolutionary conservation indicated selective pressures to maintain sequences overtime and suggests biological importance. The overlapping DMR contains a highly conserved binding motif for FOXA2, a transcription factor. Further analysis using ChIP-qPCR, reporter constructs, and siRNA, established a role for FOXA2 in regulation of MUC5B expression in lung tissue. Additionally, siRNA knock down identified 3 other transcription factors which are associated with MUC5B expression; STAT3, HOXA9 and ZBTB7A. These transcriptional regulators provide insight into possible therapeutic intervention for MUC5B dysregulation and IPF.The form and content of this abstract are approved. I recommend its publication.

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“…A recent investigation by Fingerlin et al [40 && ] identified an additional novel locus within human leukocyte antigen (HLA) complex, underscoring the potential role that impaired host defense plays in IPF pathogenesis. In addition to their association with IPF susceptibility, SNPs within MUC5B and TOLLIP have also been linked to differential survival, though the strength of association varies depending on the cohort under consideration [36,[41][42][43]. A recent pharmacogenetic investigation [44 && ] also showed that a common SNP within TOLLIP may also modulate the response to N-acetylcysteine therapy, an antioxidant commonly used to treat IPF before a phase III clinical trial failed to demonstrate efficacy [45].…”

Section: Genetic Subgroupsmentioning

confidence: 99%