Mucin 5B Promoter Polymorphism Is Associated with Susceptibility to Interstitial Lung Diseases in Chinese Males

Wang, Chunli; Yi, Zichuan; Guo, Wenwen; Cao, Lili; Zhang, Huan; Xu, Lizhi; Fan, Yida; Zhang, Deping; Wang, Yaping

doi:10.1371/journal.pone.0104919

Cited by 50 publications

(41 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Previous studies indicate that the gain‐of‐function promoter variant ( MUC5B , rs35705950) is associated with both FPF and sporadic IPF in different populations (Horimasu et al., ; Lee & Lee, ; Peljto et al., ; Seibold et al., ). In our study, the frequencies of the high risk T allele were 3.70% and 0.80% in IPF patients and healthy controls respectively ( P = 0.018), similar to previous results in Chinese and no TT homozygote was detected (Wang et al., ). Considering that IPF is a highly heterogeneous and complex disease, we performed cumulated risk analysis of four significant common SNPs (rs3737002, rs2296160, rs1800470, and rs35705950).…”

Section: Discussionsupporting

confidence: 92%

Targeted resequencing reveals genetic risks in patients with sporadic idiopathic pulmonary fibrosis

Deng

Liu

et al. 2018

Human Mutation

View full text Add to dashboard Cite

Idiopathic pulmonary fibrosis (IPF) is a genetic heterogeneous disease with high mortality and poor prognosis. However, a large fraction of genetic cause remains unexplained, especially in sporadic IPF (∼80% IPF). By systemically reviewing related literature and potential pathogenic pathways, 92 potentially IPF-related genes were selected and sequenced in genomic DNAs from 253 sporadic IPF patients and 125 matched health controls using targeted massively parallel next-generation sequencing. The identified risk variants were confirmed by Sanger sequencing. We identified two pathogenic and 10 loss-of-function (LOF) candidate variants, accounting for 4.74% (12 out of 253) of all the IPF cases. In burden tests, rare missense variants in three genes (CSF3R, DSP, and LAMA3) were identified that have a statistically significant relationship with IPF. Four common SNPs (rs3737002, rs2296160, rs1800470, and rs35705950) were observed to be statistically associated with increased risk of IPF. In the cumulative risk model, high risk subjects had 3.47-fold (95%CI: 2.07-5.81, P = 2.34 × 10 ) risk of developing IPF compared with low risk subjects. We drafted a comprehensive map of genetic risks (including both rare and common candidate variants) in patients with IPF, which could provide insights to help in understanding mechanisms, providing genetic diagnosis, and predicting risk for IPF.

show abstract

Section: Discussionsupporting

confidence: 92%

Targeted resequencing reveals genetic risks in patients with sporadic idiopathic pulmonary fibrosis

Deng

Liu

et al. 2018

Human Mutation

View full text Add to dashboard Cite

show abstract

“…Since its identification, the association between this single nucleotide polymorphism (SNP) and IPF has been replicated in 11 independent studies [48, 49, 51, 52, 76, 82, 84-86, 163, 164]. 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].…”

Section: Introductionmentioning

confidence: 96%

Regulation of MUC5B Expression in Idiopathic Pulmonary Fibrosis

Helling

Gerber

Kadiyala

et al. 2017

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

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.

show abstract

“…Among Asians, the MAF of rs35705950 is low, but in Japanese and Chinese studies, subjects with IPF had a significantly higher frequency of the risk allele than controls 13 17. The rs35705950 MAF across different ethnic groups appears to reflect disease prevalence in these groups, since NHWs have been observed to be at higher risk of pulmonary fibrosis than Hispanics, Asians and Africans 18.…”

Section: Muc5b Promoter Polymorphismmentioning

confidence: 92%

Pulmonary fibrosis in the era of stratified medicine

Mathai

Newton

Schwartz

et al. 2016

Thorax

View full text Add to dashboard Cite

Both common and rare variants contribute to the genetic architecture of pulmonary fibrosis. Genome-wide association studies have identified common variants, or those with a minor allele frequency of >5%, that are linked to pulmonary fibrosis. The most widely replicated variant (rs35705950) is located in the promoter region of the MUC5B gene and has been strongly associated with idiopathic pulmonary fibrosis (IPF) and familial interstitial pneumonia (FIP) across multiple different cohorts. However, many more common variants have been identified with disease risk and in aggregate account for approximately one-third of the risk of IPF. Moreover, several of these common variants appear to have prognostic potential. Next generation sequencing technologies have facilitated the identification of rare variants. Recent whole exome sequencing studies have linked pathogenic rare variants in multiple new genes to FIP. Compared with common variants, rare variants have lower population allele frequencies and higher effect sizes. Pulmonary fibrosis rare variants genes can be subdivided into two pathways: telomere maintenance and surfactant metabolism. Heterozygous rare variants in telomere-related genes co-segregate with adult-onset pulmonary fibrosis with incomplete penetrance, lead to reduced protein function, and are associated with short telomere lengths. Despite poor genotype-phenotype correlations, lung fibrosis associated with pathogenic rare variants in different telomere genes is progressive and displays similar survival characteristics. In contrast, many of the heterozygous rare variants in the surfactant genes predict a gain of toxic function from protein misfolding and increased endoplasmic reticulum (ER) stress. Evidence of both telomere shortening and increased ER stress have been found in sporadic IPF patients, suggesting that the mechanisms identified from rare variant genetic studies in unique individuals and families are applicable to a wider spectrum of patients. The ability to sequence large cohorts of individuals rapidly has the potential to further our understanding of the relative contributions of common and rare variants in the pathogenesis of pulmonary fibrosis. The UK 100,000 Genomes Project will provide opportunities to interrogate both common and rare variants and to investigate how these biological signals provide diagnostic and prognostic information in the era of stratified medicine.

show abstract

Mucin 5B Promoter Polymorphism Is Associated with Susceptibility to Interstitial Lung Diseases in Chinese Males

Cited by 50 publications

References 45 publications

Targeted resequencing reveals genetic risks in patients with sporadic idiopathic pulmonary fibrosis

Targeted resequencing reveals genetic risks in patients with sporadic idiopathic pulmonary fibrosis

Regulation of MUC5B Expression in Idiopathic Pulmonary Fibrosis

Pulmonary fibrosis in the era of stratified medicine

Contact Info

Product

Resources

About