Sequencing of idiopathic pulmonary fibrosis-related genes reveals independent single gene associations

Coghlan, Meghan A; Shifren, Adrián; Huang, Howard J.; Russell, Tonya; Mitra, Robi D.; Zhang, Qunyuan; Wegner, Daniel; Cole, F. Sessions; Hamvas, Aaron

doi:10.1136/bmjresp-2014-000057

Cited by 72 publications

(59 citation statements)

References 38 publications

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“…Transmission is autosomal dominant [90,91]. In selected cases of familial ILD, study of SFTPA2, SFTPC and ABCA3 allowed a genetic cause to be identified in 6.5% of families [92].…”

Section: Surfactant Protein Mutationsmentioning

confidence: 99%

Management of suspected monogenic lung fibrosis in a specialised centre

et al. 2017

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At least 10% of patients with interstitial lung disease present monogenic lung fibrosis suspected on familial aggregation of pulmonary fibrosis, specific syndromes or early age of diagnosis. Approximately 25% of families have an identified mutation in genes mostly involved in telomere homeostasis, and more rarely in surfactant homeostasis.Beyond pathophysiological knowledge, detection of these mutations has practical consequence for patients. For instance, mutations involved in telomere homeostasis are associated with haematological complications after lung transplantation and may require adapted immunosuppression. Moreover, relatives may benefit from a clinical and genetic evaluation that should be specifically managed.The field of genetics of pulmonary fibrosis has made great progress in the last 10 years, raising specific problems that should be addressed by a specialised team.

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“…Transmission is autosomal dominant [90,91]. In selected cases of familial ILD, study of SFTPA2, SFTPC and ABCA3 allowed a genetic cause to be identified in 6.5% of families [92].…”

Section: Surfactant Protein Mutationsmentioning

confidence: 99%

Management of suspected monogenic lung fibrosis in a specialised centre

et al. 2017

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“…Premature infants with underdeveloped lungs often become hypoxic and die due to a high surface tension at the epithelial layer due to the under-expression of surfactant lipids [69,70]. In IPF, mutations occur in the surfactant genes SFTPC [71][72][73][74], SFTPA2 [75], and ABCA3 [76]. The IPF variants in these genes lead to misfolded and shortened proteins and aberrant expression [77].…”

Section: Surfactantmentioning

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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“…The disease is characterised by progressive worsening of dyspnoea and lung function and is generally associated with a poor prognosis (1). Although the aetiology of IPF is unknown, the pathogenesis is believed to involve both genetic predisposition and environmental risk factors, including smoking, exposure to metal and wood dust, gastro-oesophageal reflux disease (GORD) and even some viral infections (2).…”

Section: Introductionmentioning

confidence: 99%