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

Peljto, Anna L.; Selman, Moisés; Kim, Dong Soon; Murphy, Elissa; Tucker, Laura; Pardo, Annie; Lee, Jung Su; Ji, Wonjun; Schwarz, Marvin I.; Yang, Ivana V.; Schwartz, David A.; Fingerlin, Tasha E.

doi:10.1378/chest.14-0867

Cited by 109 publications

(84 citation statements)

References 17 publications

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“…This association, however, may be specific to IIP among interstitial lung diseases (ILD) since reports indicate rs35705950 does not confer increased risk of scleroderma-related ILD or sarcoidosis [39, 42, 45]. This association of rs35705950 with IPF was confirmed in a cohort of Mexican patients [46]; however, rs35705950 was found to be rare in a Korean cohort of IPF patients. Similarly, in a Chinese population, rs35705950 was rare in IPF patients but different MUC5B polymorphisms were associated with disease [47].…”

Section: Common Genetic Variants In Ipfmentioning

confidence: 97%

The genetic basis of idiopathic pulmonary fibrosis

2015

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Throughout the past decade, there have been substantial advances in understanding the pathogenesis of idiopathic pulmonary fibrosis (IPF). Recently, several large genome-wide association and linkage studies have identified common genetic variants in more than a dozen loci that appear to contribute to IPF risk. In addition, family-based studies have led to the identification of rare genetic variants in genes related to surfactant function and telomere biology, and mechanistic studies suggest pathophysiologic derangements associated with these rare genetic variants are also found in sporadic cases of IPF. Current evidence suggests that rather than existing as distinct syndromes, sporadic and familial cases of IPF (Familial Interstitial Pneumonia, FIP) likely reflect a continuum of genetic risk. Rapidly evolving bioinformatic and molecular biology techniques, combined with next-generation sequencing technologies, hold great promise for developing a comprehensive, integrated approach to defining the fundamental molecular mechanisms that underlie IPF pathogenesis.

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Section: Common Genetic Variants In Ipfmentioning

confidence: 97%

The genetic basis of idiopathic pulmonary fibrosis

2015

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“…The MUC5B rs35705950T allele is the strongest risk factor identified thus far, accounting for 30%–35% of the risk of developing IPF 55 57–60. The frequency of the mutant allele is lower among Asian patients (approximately 7% vs <2% in healthy controls), but the risk associated with its carriage appears comparable to that observed among European ancestry 61 62. Notably, the MUC5B association is specific for IPF,58 59 63 suggesting both a role for MUC5B rs35705950T in disease pathogenesis and the existence of major differences in genetic susceptibility across the spectrum of fibrotic lung diseases 25…”

Section: Introductionmentioning

confidence: 95%

Genetics of idiopathic pulmonary fibrosis: from mechanistic pathways to personalised medicine

Spagnolo

Cottin

2016

J Med Genet

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Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and ultimately fatal disorder for which there is no cure. While the disease is by definition idiopathic, accumulating evidence, including familial aggregation of cases and the occurrence of pulmonary fibrosis in the context of a number of rare genetic disorders, indicates that genetic factors contribute significantly to the pathogenesis of IPF. Several disease-associated genetic variants, both rare and common, have been identified in familial and sporadic IPF. While the full clinical implications of these genetic associations remain to be elucidated, observational studies suggest that genotype influences the development of the disease and its outcome. Available data indicate that genetics has the potential to identify individuals at risk of IPF, classify patients more precisely, clarify the key pathways involved in disease pathogenesis and eventually develop more effective targeted therapies. Considerable research is required before a comprehensive disease fingerprint of IPF can be delivered. Nevertheless, the application of rapidly evolving molecular biology and genomic technologies combined with appropriate bioinformatic methodology offers an unprecedented and realistic opportunity to achieve this goal.

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“…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

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

Cited by 109 publications

References 17 publications

The genetic basis of idiopathic pulmonary fibrosis

The genetic basis of idiopathic pulmonary fibrosis

Genetics of idiopathic pulmonary fibrosis: from mechanistic pathways to personalised medicine

Regulation of MUC5B Expression in Idiopathic Pulmonary Fibrosis

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