Mucin 5B promoter polymorphism is associated with idiopathic pulmonary fibrosis but not with development of lung fibrosis in systemic sclerosis or sarcoidosis

Stock, Carmel; Sato, Hajime; Fonseca, Carmen; Banya, Winston; Molyneaux, Philip L.; Adamali, Huzaifa; Russell, Anne-Marie; Denton, Christopher P.; Abraham, David; Hansell, David M.; Nicholson, Andrew G.; Maher, Toby M.; Wells, Athol U.; Lindahl, Gisela; Renzoni, Elisabetta A.

doi:10.1136/thoraxjnl-2012-201786

Cited by 199 publications

(159 citation statements)

References 36 publications

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“…We also recently identified two molecular subtypes of IPF based on a strong gene expression signature of cilium-associated genes [22]. Interestingly, expression of MUC5B, the strongest and most replicated genetic risk factor for IPF [19,[47][48][49][50][51][52], is highly correlated to expression of cilium genes. Furthermore, MUC5B expression is also associated with expression of MMP7, an extracellular matrix gene that has emerged as a significant expression biomarker for IPF [41,44,53] and was recently shown to play a role in attenuating ciliated cell differentiation during wound repair [54].…”

Section: Chapter I Genetics and Epigenetics Of Idiopathic Pulmonary Fmentioning

confidence: 99%

“…As such, the relationship between rs35705950 and increased risk of ILD in these syndromes was investigated. Several studies determined that rs35705950 was not associated with the development of interstitial pneumonia or pulmonary fibrosis in systemic sclerosis, sarcoidosis, or connective tissue associated ILD [48,51,83,168]. However, the variant was associated with a pooled group of 'other ILDs' when IPF was removed from the group suggesting that some ILDs may share the rs35705950 risk variant [175].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Chapter I Genetics and Epigenetics Of Idiopathic Pulmonary Fmentioning

confidence: 99%

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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“…[3][4][5] Of note, a promoter polymorphism in MUC5B has been confi rmed by multiple studies as a common risk factor with the largest genetic eff ect on development of pulmonary fi brosis, estimated to increase risk by sixfold for people who are heterozygous for the polymorphism and by 20-fold for those who are homozygous . [1][2][3]6,7 Th e identifi cation of these loci, and of the MUC5B polymorphism, in particular, have changed perspectives on the pathogenesis of pulmonary fi brosis, motivated additional research on the risk factors for pulmonary fi brosis, and generated new targets for pharmacologic therapies. 3,[8][9][10] While research on the genetics of pulmonary fi brosis is making great progress, these studies share an important limitation: All were conducted in populations of non-Hispanic white subjects only.…”

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confidence: 99%

The MUC5B Promoter Polymorphism Is Associated With Idiopathic Pulmonary Fibrosis in a Mexican Cohort but Is Rare Among Asian Ancestries

Peljto¹,

Selman

Kim

et al. 2015

Chest

105

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BACKGROUND:Polymorphisms in the MUC5B promoter, TOLLIP , and nine additional genetic loci have been associated with idiopathic pulmonary fi brosis (IPF) within non-Hispanic white populations. It is unknown whether these variants account for risk of IPF in other racial/ethnic populations. We conducted a candidate single nucleotide polymorphism (SNP) association study in cohorts of Mexican and Korean patients with IPF.

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“…Specific examples Review Article on From Microbe to Microbiome: New Implication in Respiratory & Critical Care Medicine include a single nucleotide polymorphism (SNP) in the promoter region of mucin 5B gene (MUC5B) (rs35705950) encoding a key component of airway mucus, and a SNP in the toll-interacting protein (TOLLIP) gene (rs5743890) encoding an adaptor protein which modulates signalling through toll-like receptors (TLRs) (7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

The Respiratory Microbiome In Idiopathic Pulmonary Fibrosis

Molyneaux¹,

Russell²,

Cox³

et al. 2012

C103. Pathogenesis, Biomarkers, and Risk Factors for Interstitial Lung Disease: From Bench to Bedside

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Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease of unknown cause. Current evidence suggests that it arises in genetically susceptible individuals as a consequence of an aberrant wound-healing response following repetitive alveolar injury. Overt respiratory infection and immunosuppression carry a high mortality, while polymorphisms in genes related to epithelial integrity and host defence predispose to IPF. Recent advances in sequencing technologies have allowed the use of molecular microbial technologies to characterise the respiratory microbiota in patients with IPF. Studies have suggested that changes in the overall bacterial burden are related to disease progression and highlighted significant differences between the microbiota in IPF subjects and healthy controls. Indeed differences in the microbiota between IPF patients may differentiate those with stable compared to progressive disease. As our understanding of the IPF microbiome evolves, along with refinement and advances in sampling and sequencing methodologies we may be able to use microbial signatures as a biomarker to guide prognostication and even treatment stratification in this devastating disease.

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Mucin 5B promoter polymorphism is associated with idiopathic pulmonary fibrosis but not with development of lung fibrosis in systemic sclerosis or sarcoidosis

Cited by 199 publications

References 36 publications

Regulation of MUC5B Expression in Idiopathic Pulmonary Fibrosis

Regulation of MUC5B Expression in Idiopathic Pulmonary Fibrosis

The MUC5B Promoter Polymorphism Is Associated With Idiopathic Pulmonary Fibrosis in a Mexican Cohort but Is Rare Among Asian Ancestries

The Respiratory Microbiome In Idiopathic Pulmonary Fibrosis

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