MUC5B Promoter Variant rs35705950 Affects MUC5B Expression in the Distal Airways in Idiopathic Pulmonary Fibrosis.
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ABSTRACT:
SUBMITTER: Nakano Y
PROVIDER: S-EPMC4803086 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: Not available
| S-EPMC4327944 | biostudies-literature
Project description:MUC5B promoter rs35705950 T/G gene polymorphism has been associated with the risk of IPF, but the influence of this relationship varies among different populations. In the past 2 years, there were new clinical studies with different results, but none of them reached unified conclusions. Therefore, this study further included the latest case-control studies, integrated their results and carried out meta-analysis on them to draw reliable conclusions. PubMed, EMBASE, CNKI, Wanfang database and VIP Chinese science were searched by a computer to collect the related literatures of MUC5B gene polymorphism and IPF susceptibility published before June 15, 2021. The first author, year of publication, diagnostic criteria and gene frequency were extracted after screened them. Forest plot was drawn and the trial sequential analysis (TSA) was carried out to confirm the stability of the meta-analysis results. Registration number: CRD42021272940. A total of 24 case-control studies (13 studies on the Caucasian, 7 studies on the Asian and 4 studies on the mixed population), and a total of 6749 IPF patients and 13,898 healthy controls were included in this study. The T vs.G, TT vs. GG, GT vs. GG, GT + TT vs. GG and TT vs. GG + GT genetic models of MUC5B promoter rs35705950 T/G polymorphism were associated with IPF risk in all populations, and the effect values were ([OR] 4.12, 95% CI [3.64, 4.67]), ([OR] 10.12, 95% CI [7.06, 14.49]), ([OR] 4.84, 95% CI [3.85, 6.08]), ([OR] 4.84, 95% CI [3.79, 6.19]) and ([OR] 5.11, 95% CI [4.02, 6.49]), respectively. The results of TSA confirmed the stability of the results. Subgroup analysis showed that T vs.G, TT vs. GG, GT vs. GG, GT + TT vs. GG and TT vs. GG + GT genetic models of MUC5B polymorphism were associated with IPF risk in Caucasian population. The effect values were ([OR] 4.50, 95% CI [3.93, 5.16]), ([OR] 10.98, 95% CI [7.59, 15.89]), ([OR] 6.27, 95% CI [5.37, 7.32]), ([OR] 6.30, 95% CI [5.19, 7.64]) and ([OR] 5.15, 95% CI [4.01, 6.61]), respectively. Similar results were also found in Asian and mixed populations. The association strength of the minor T allele in the Caucasian was more significant than that of the Asian population ([OR] 4.50 vs. [OR] 2.39), and the association strength of all genetic models carrying "T" was more significant than that of the Asian population ([OR] 10.98 vs. [OR] 4.29). In Caucasian, Asian and mixed populations, T minor allele carriers were more likely to be susceptible to pulmonary fibrosis, and TT genotype carriers were more likely to be susceptible to IPF than GT genotype carriers. The association between IPF and Caucasian population with minor T allele and all "T" genetic model was more significant than that of Asian population.
| S-EPMC8671516 | biostudies-literature
Project description:Rationale: The goal was to connect elements of idiopathic pulmonary fibrosis (IPF) pathogenesis, including chronic endoplasmic reticulum stress in respiratory epithelia associated with injury/inflammation and remodeling, distal airway mucus obstruction and honeycomb cyst formation with accumulation of MUC5B (mucin 5B), and associations between IPF risk and polymorphisms in the MUC5B promoter. Objectives: To test whether the endoplasmic reticulum (ER) stress sensor protein ERN2 (ER-to-nucleus signaling 2) and its downstream effector, the spliced form of XBP1S (X-box-binding protein 1), regulate MUC5B expression and differentially activate the MUC5B promoter variant in respiratory epithelia. Methods: Primary human airway epithelial (HAE) cells, transgenic mouse models, human IPF lung tissues, and cell lines expressing XBP1S and MUC5B promoters were used to explore relationships between the ERN2/XBP1S pathway and MUC5B. An inhibitor of the pathway, KIRA6, and XBP1 CRISPR-Cas9 were used in HAE cells to explore therapeutic potential. Measurements and Main Results: ERN2 regulated MUC5B and MUC5AC mRNAs. Downstream XBP1S selectively promoted MUC5B expression in vitro and in distal murine airway epithelia in vivo. XBP1S bound to the proximal region of the MUC5B promoter and differentially upregulated MUC5B expression in the context of the MUC5B promoter rs35705950 variant. High levels of ERN2 and XBP1S were associated with excessive MUC5B mRNAs in distal airways of human IPF lungs. Cytokine-induced MUC5B expression in HAE cells was inhibited by KIRA6 and XBP1 CRISPR-Cas9. Conclusions: A positive feedback bistable ERN2-XBP1S pathway regulates MUC5B-dominated mucus obstruction in IPF, providing an unfolded protein response-dependent mechanism linking the MUC5B promoter rs35705950 polymorphism with IPF pathogenesis. Inhibiting ERN2-dependent pathways/elements may provide a therapeutic option for IPF.
| S-EPMC6635783 | biostudies-literature
Project description:BackgroundA common variant located in the promoter region of MUC5B (rs35705950) is the strongest risk factor for sporadic and familiar IPF, as well as a predictor of outcome. However, there are no data on the effect of MUC5B rs35705950 genotype on the prognosis of IPF patients on antifibrotic treatment. The aim of this study is to determine, in a phenotypically well-characterized population of patients with IPF treated with antifibrotics, the impact of MUC5B rs35705950 genotype on disease progression and survival.Methods88 IPF patients on antifibrotic treatment were followed-up from 2014 until transplantation, death or end of follow-up (December 2019). Disease progression was defined as a forced vital capacity (FVC) loss ≥ 5% per year. All patients were genotyped for MUC5B rs35705950 by PCR amplification and Sanger sequencing.ResultsOut of 88 patients, 61 (69%) carried the mutant T allele (TT or TG) and 27 (31%) did not (GG). Carriage of the MUC5B rs35705950 T allele was not associated with a faster decline in FVC. Conversely, at the end of the follow-up, overall survival in carriers of the TT/TG genotype was longer compared to that of the GG genotype carriers. FVC (L) at baseline and time to respiratory failure at rest were independent predictors of worse prognosis.ConclusionsIn IPF patients on antifibrotic treatment, carriage of the MUC5B rs35705950 T allele is associated with longer survival, highlighting the usefulness of MUC5B genetic data in clinical decision making.
| S-EPMC8017848 | biostudies-literature
Project description:Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a poor prognosis. A number of studies reported the association between MUC5B promoter polymorphism rs35705950 and IPF, but substantial inconsistent findings were observed and the strength of association remains unclear.The aim of the study was to investigate the association between rs35705950 and IPF in different ethnic populations.PubMed, EMBASE, Web of Science, and CENTRAL were searched from their inception to April 15, 2015. Allelic and phenotypic comparisons were conducted separately, as were comparisons in Caucasian and Asian populations. A meta-analysis with trial sequential analysis was conducted.Nine studies presented in 7 full-text articles were included, encompassing 2733 IPF patients and 5044 controls. Six studies were carried out in the Caucasian population, and 3 in the Asian population. Minor T allele was associated with an increased risk of IPF compared with G allele (odds ratio [OR] 4.85, 95% confidence interval [CI] 3.79-6.21, P = 5.88 × 10), as were TG and TT genotypes compared with GG genotype (TG vs GG: OR 6.20, 95% CI 5.14-7.48, P = 1.70 × 10; TT vs GG: OR 11.29, 95% CI 5.69-22.40, P = 4.22 × 10), in an allele dose-dependent manner. These observations were confirmed in trial sequential analysis in both populations. The strength of association was more remarkable in the Caucasian population than in the Asian population, and no homozygous TT genotype was detected in the Asian population in our study.Our study revealed strong association between the MUC5B promoter rs35705950 polymorphism and the risk of IPF. The strength of association between rs35705950 minor T allele and IPF susceptibility was particularly evident in the Caucasian population, and milder but still significant in the Asian population.
| S-EPMC4972586 | biostudies-literature
Project description:Idiopathic pulmonary fibrosis (IPF), a fatal disease that is a result of complex interactions between genetics and the environment, has limited treatment options. We have identified the MUC5B promoter polymorphism and other common genetic variants that in aggregate explain roughly one-third of disease risk. The MUC5B promoter polymorphism is the strongest and the most replicated genetic risk factor for IPF, appears to be protective and predictive in this disease, and is likely involved in disease pathogenesis through an increase in MUC5B expression in terminal bronchi and honeycombed cysts. Expression of MUC5B is also highly correlated with expression of cilium genes in IPF lung. Our work suggests that mucociliary dysfunction in the distal airway may play a role in the development of progressive fibroproliferative lung disease. In addition, our work has important implications for secondary prevention, early detection, and future early and personalized treatment based on genetic profiles.
| S-EPMC4722833 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-12-29 | GSE157691 | GEO
Project description:Current prediction models of mortality in idiopathic pulmonary fibrosis (IPF), which are based on clinical and physiological parameters, have modest value in predicting which patients will progress. In addition to the potential for improving prognostic models, identifying genetic and molecular features that are associated with IPF mortality may provide insight into the underlying mechanisms of disease and inform clinical trials.To determine whether the MUC5B promoter polymorphism (rs35705950), previously reported to be associated with the development of pulmonary fibrosis, is associated with survival in IPF.Retrospective study of survival in 2 independent cohorts of patients with IPF: the INSPIRE cohort, consisting of patients enrolled in the interferon-?1b trial (n = 438; December 15, 2003-May 2, 2009; 81 centers in 7 European countries, the United States, and Canada), and the Chicago cohort, consisting of IPF participants recruited from the Interstitial Lung Disease Clinic at the University of Chicago (n = 148; 2007-2010). The INSPIRE cohort was used to model the association of the MUC5B genotype with survival, accounting for the effect of matrix metalloproteinase 7 (MMP-7) blood concentration and other demographic and clinical covariates. The Chicago cohort was used for replication of findings.The primary end point was all-cause mortality.The numbers of patients in the GG, GT, and TT genotype groups were 148 (34%), 259 (59%), and 31 (7%), respectively, in the INSPIRE cohort and 41 (28%), 98 (66%), and 9 (6%), respectively, in the Chicago cohort. The median follow-up period was 1.6 years for INSPIRE and 2.1 years for Chicago. During follow-up, there were 73 deaths (36 GG, 35 GT, and 2 TT) among INSPIRE patients and 64 deaths (26 GG, 36 GT, and 2 TT) among Chicago patients. The unadjusted 2-year cumulative incidence of death was lower among patients carrying 1 or more copies of the IPF risk allele (T) in both the INSPIRE cohort (0.25 [95% CI, 0.17-0.32] for GG, 0.17 [95% CI, 0.11-0.23] for GT, and 0.03 [95% CI, 0.00-0.09] for TT) and the Chicago cohort (0.50 [95% CI, 0.31-0.63] for GG, 0.22 [95% CI, 0.13-0.31] for GT, and 0.11 [95% CI, 0.00-0.28] for TT). In the INSPIRE cohort, the TT and GT genotypes (risk for IPF) were associated with improved survival compared with GG (hazard ratios, 0.23 [95% CI, 0.10-0.52] and 0.48 [95% CI, 0.31-0.72], respectively; P < .001). This finding was replicated in the Chicago cohort (hazard ratios, 0.15 [95% CI, 0.05-0.49] and 0.39 [95% CI, 0.21-0.70], respectively; P < .002). The observed association of MUC5B with survival was independent of age, sex, forced vital capacity, diffusing capacity of carbon monoxide, MMP-7, and treatment status. The addition of the MUC5B genotype to the survival models significantly improved the predictive accuracy of the model in both the INSPIRE cohort (C = 0.71 [95% CI, 0.64-0.75] vs C = 0.68 [95% CI, 0.61-0.73]; P < .001) and the Chicago cohort (C = 0.73 [95% CI, 0.62-0.78] vs C = 0.69 [95% CI, 0.59-0.75]; P = .01).Among patients with IPF, a common risk polymorphism in MUC5B was significantly associated with improved survival. Further research is necessary to refine the risk estimates and to determine the clinical implications of these findings.
| S-EPMC4545271 | biostudies-literature
Project description:The gain-of-function mucin 5B (MUC5B) promoter variant, rs35705950, confers the largest risk, genetic or otherwise, for the development of idiopathic pulmonary fibrosis; however, the mechanisms underlying the regulation of MUC5B expression have yet to be elucidated. Here, we identify a critical regulatory domain that contains the MUC5B promoter variant and has a highly conserved forkhead box protein A2 (FOXA2) binding motif. This region is differentially methylated in association with idiopathic pulmonary fibrosis, MUC5B expression, and rs35705950. In addition, we show that this locus binds FOXA2 dynamically, and that binding of FOXA2 is necessary for enhanced expression of MUC5B. In aggregate, our findings identify novel targets to regulate the expression of MUC5B.
| S-EPMC5516283 | biostudies-literature
Project description:The G/T transversion, rs35705950, located approximately 3 kb upstream of the MUC5B start site, is the cardinal risk factor for IPF. Here, we investigate the function and chromatin structure of this -3 kb region and provide evidence that it functions as a classically defined enhancer subject to epigenetic programming. We use nascent transcript analysis to show that RNA polymerase II loads within 10 bp of the G/T transversion site, definitively establishing enhancer function for the region. By integrating ATAC-seq analysis of fresh and cultured human airway epithelial cells with nuclease sensitivity data, we demonstrate that this region is in accessible chromatin that affects the expression of MUC5B. Through applying paired single nucleus RNA- and ATAC-seq to frozen tissue from IPF lungs, we extend these findings directly to disease, with results indicating that epigenetic programming of the -3 kb enhancer in IPF occurs in both MUC5B-expressing and non-expressing lineages. In aggregate, our results indicate that the MUC5B-associated variant, rs35705950, resides within an enhancer that is subject to epigenetic remodeling and contributes to pathologic misexpression in IPF.
2020-12-29 | GSE157606 | GEO