Idiopathic Pulmonary Fibrosis: Patient Attitudes towards Invasive Ventilation and Insight into Disease.

Genome-wide association studies have identified 14 genetic loci associated with susceptibility to idiopathic pulmonary fibrosis (IPF), a devastating lung disease with poor prognosis. Of these, the variant with the strongest association, rs35705950, is located in the promoter region of the MUC5B gene and has a risk allele (T) frequency of 30-35% in IPF cases. Here we present estimates of the proportion of disease liability explained by each of the 14 IPF risk variants as well as estimates of the proportion of cases that can be attributed to each variant. We estimate that rs35705950 explains 5.9-9.4% of disease liability, which is much lower than previously reported estimates. Of every 100,000 individuals with the rs35705950_GG genotype we estimate 30 will have IPF, whereas for every 100,000 individuals with the rs35705950_GT genotype 152 will have IPF. Quantifying the impact of genetic risk factors on disease liability improves our understanding of the underlying genetic architecture of IPF and provides insight into the impact of genetic factors in risk prediction modelling.

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A MUC5B polymorphism associated with Idiopathic Pulmonary Fibrosis mediates overexpression through decreased CpG methylation and C/EBPβ transcriptional activation

10.1101/2019.12.18.880674 ◽

2019 ◽

Author(s):

Amaranta U. Armesto-Jimenez ◽

Ari J. Arason ◽

Olafur A. Stefansson ◽

Gunnar Gudmundsson ◽

Thorarinn Gudjonsson ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Transcriptional Activation ◽

Risk Allele ◽

Promoter Polymorphism ◽

Regulatory Factor ◽

Combined Mechanism ◽

Regulatory Effects ◽

Factor C ◽

Insight Into

AbstractIdiopathic pulmonary fibrosis is a progressive and fatal lung disease of unknown aetiology. The strongest genetic risk factor associated with IPF development is a MUC5B promoter polymorphism (rs35705950). However, the mechanism underlying its effects remains unknown. In this study we have focused on the molecular consequences of the polymorphism on the regulation of MUC5B expression. We have identified a combined mechanism involving both methylation and direct transcriptional regulation mediated by the polymorphic variant on MUC5B overexpression. Our results demonstrate that the minor allele (T) associated with rs35705950 disturbs a DNA methylation site, directly increasing MUC5B expression. Furthermore, this same variant also creates a novel binding site for the transcription factor C/EBPβ leading to transcriptional activation of MUC5B. Our findings provide a novel insight into the regulatory effects of the IPF risk allele, rs35705950 and identifies C/EBPβ as an important regulatory factor in the development of IPF.

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Cough in idiopathic pulmonary fibrosis

European Respiratory Review ◽

10.1183/16000617.0090-2015 ◽

2016 ◽

Vol 25 (141) ◽

pp. 278-286 ◽

Cited By ~ 47

Author(s):

Mirjam J.G. van Manen ◽

Surinder S. Birring ◽

Carlo Vancheri ◽

Vincent Cottin ◽

Elisabetta A. Renzoni ◽

...

Keyword(s):

Quality Of Life ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Chronic Cough ◽

Future Developments ◽

New Compounds ◽

Insight Into ◽

Made In ◽

Gaining Insight

Many patients with idiopathic pulmonary fibrosis (IPF) complain of chronic refractory cough. Chronic cough is a distressing and disabling symptom with a major impact on quality of life. During recent years, progress has been made in gaining insight into the pathogenesis of cough in IPF, which is most probably “multifactorial” and influenced by mechanical, biochemical and neurosensory changes, with an important role for comorbidities as well. Clinical trials of cough treatment in IPF are emerging, and cough is increasingly included as a secondary end-point in trials assessing new compounds for IPF. It is important that such studies include adequate end-points to assess cough both objectively and subjectively. This article summarises the latest insights into chronic cough in IPF. It describes the different theories regarding the pathophysiology of cough, reviews the different methods to assess cough and deals with recent and future developments in the treatment of cough in IPF.

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