Chronic obstructive pulmonary disease: A guide for the primary care physician

Mehta, Gautam R.; Mohammed, Rafat; Sarfraz, Sarah; Khan, Tajwaar; Ahmed, Khansa; Villareal, Mauricio; Martinez, Dennis; Iskander, Joy; Mohammed, Rachid

doi:10.1016/j.disamonth.2016.03.002

Cited by 2 publications

(1 citation statement)

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“…COPD is characterized by chronic inflammation in the lung, dyspnea, emphysema, cough, and airway obstruction and is primarily associated with cigarette using [202,203]. Although COPD is one of the most well studied ILDs, there are no cures and response to treatment can be unpredictable [204].…”

Section: Chronic Obstructive Pulmonary Diseasementioning

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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Section: Chronic Obstructive Pulmonary Diseasementioning

confidence: 99%