Genetic Control of Fatty Acid β-Oxidation in Chronic Obstructive Pulmonary Disease

Jiang, Zhiqiang; Knudsen, Nelson H.; Wang, Gang; Qiu, Weiliang; Naing, Zun Zar Chi; Bai, Yan; Ai, Xingbin; Lee, Chih‐Hao; Zhou, Xiaobo

doi:10.1165/rcmb.2016-0282oc

Cited by 61 publications

(58 citation statements)

References 47 publications

(58 reference statements)

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“…Two of these, CPT1A and SGK1, are important factors in COPD pathogenesis. While CPT1A is a cigarette smoke-inducible regulator of fatty acid oxidation 35 , SGK1 increases CFTR, which might be a counter-mechanism to the observed down-regulation of CFTR in COPD 36,37 . Another miR-365 target, RHEBL1, activates mTOR signalling 38 , which controls cell proliferation via SGK1 39 .…”

Section: Discussionmentioning

confidence: 96%

Transcriptional analysis identifies potential biomarkers and molecular regulators in pneumonia and COPD exacerbation

Bertrams

Griss

Han

et al. 2020

Sci Rep

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Lower respiratory infections, such as community-acquired pneumonia (cAp), and chronic obstructive pulmonary disease (copD) rank among the most frequent causes of death worldwide. improved diagnostics and profound pathophysiological insights are urgent clinical needs. in our cohort, we analysed transcriptional networks of peripheral blood mononuclear cells (pBMcs) to identify central regulators and potential biomarkers. We investigated the mRnA-and miRnA-transcriptome of pBMcs of healthy subjects and patients suffering from CAP or AECOPD by microarray and Taqman Low Density Array. Genes that correlated with PBMC composition were eliminated, and remaining differentially expressed genes were grouped into modules. One selected module (120 genes) was particularly suitable to discriminate AECOPD and CAP and most notably contained a subset of five biologically relevant mRNAs that differentiated between CAP and AECOPD with an AUC of 86.1%. Likewise, we identified several microRNAs, e.g. miR-545-3p and miR-519c-3p, which separated AECOPD and CAP. We furthermore retrieved an integrated network of differentially regulated mRNAs and microRNAs and identified HNF4A, MCC and MUC1 as central network regulators or most important discriminatory markers. in summary, transcriptional analysis retrieved potential biomarkers and central molecular features of cAp and AecopD. Community acquired pneumonia (CAP) is clinically defined by a sudden onset of severe illness that is accompanied by signs of lower respiratory tract infection, fever, cough and dyspnoea 1. When left untreated, severe secondary effects such as organ damage and occurrence of bacteria in the blood (bacteremia) can ensue. While subject to variance due to region, season and population characteristics, the incidence of CAP is estimated to lie between 1.5 and 14 cases per 1,000 persons per year, with children under 5 years of age and the elderly of more than 65 years being most strongly affected 2. Immunocompromised persons also bear a higher risk of CAP contraction. The leading underlying cause of CAP is infection with the gram-positive bacterium Streptococcus pneumoniae, accounting for 30-35% of CAP cases worldwide 3. The initial colonization of the nasopharynx and the upper respiratory tract often remains asymptomatic. Aspiration into the alveoli can cause severe respiratory or systemic disease, depending on the host immune status and the pneumococcal serotype 1. As CAP is a multifaceted disease with a host of potential causative agents, the robust identification of microR-NAs that are functionally involved in pneumonia depends on the pathogen. In severe Influenza A Virus (H1N1)

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Section: Discussionmentioning

confidence: 96%

Transcriptional analysis identifies potential biomarkers and molecular regulators in pneumonia and COPD exacerbation

Bertrams

Griss

Han

et al. 2020

Sci Rep

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“…Nowadays, COPD has become the third source of morbidity in the world. 1 Although tobacco smoking has been suggested to be the predominant environmental factor for COPD, only ~10%–20% smokers develop airway obstruction. 2 This phenomenon, together with the familial clustering in COPD patients, 3 , 4 indicates that genetic factors might play an important role in the development of COPD.…”

Section: Introductionmentioning

confidence: 99%

A functional SNP upstream of the <em>ADRB2</em> gene is associated with COPD

Fu²,

Zhang

et al. 2018

COPD

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BackgroundPrevious studies have suggested that β2-adrenergic receptor (ADRB2) is associated with COPD. However, the role of genetic polymorphisms in ADRB2 on COPD has not been evaluated yet.MethodsIn this study, SNaPshot genotyping, luciferase assay, chromatin immunoprecipitation and real-time polymerase chain reaction were adopted to investigate the association between ADRB2 genetic polymorphisms and COPD, comprehensively.ResultsOne single nucleotide polymorphism (rs12654778), located upstream of ADRB2, showed a significant association with COPD by the logistic regression analysis after adjusting for age, sex and smoking history (p=0.04) in 200 COPD patients and 222 controls from southwest Chinese population. Furthermore, the luciferase assay indicated that rs12654778-A allele reduced the relative promoter activity by ~26% compared with rs12654778-G allele (p=0.0034). The chromatin immunoprecipitation analysis demonstrated that rs12654778 modulated the binding affinity of transcription factor neurofibromin 1. In addition, a significantly reduced expression of ADRB2 in COPD patients was observed, compared with normal controls (p=0.017).ConclusionOur findings suggest a previously unknown mechanism linking allele-specific effects of rs12654778 on ADRB2 expression to COPD onset, for the first time.

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“…COPD is one of the most common respiratory diseases in older people, and the third cause of morbidity and mortality worldwide, with a high and growing prevalence. 1 …”

Section: Introductionmentioning

confidence: 99%

Effects of a single long-acting muscarinic antagonist agent and a long-acting muscarinic antagonist/long-acting β2-adrenoceptor agonist combination on lung function and symptoms in untreated COPD patients in Japan

Hida¹,

Hizawa²

2018

COPD

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BackgroundA large body of evidence suggests that long-acting β2-adrenoceptor agonist (LABA)/long-acting muscarinic antagonist (LAMA) combinations induce a strong synergistic bronchodilatory effect in human isolated airways. Moreover, a recent post hoc analysis demonstrated clinical synergism between LABAs and LAMAs, which induces a synergistic improvement not only in lung function but also in dyspnea in COPD patients.AimThe aim of this study is to examine the baseline factors related to improvement in lung function or clinical symptoms that results from the administration of LAMA or LAMA/LABA and to compare the differences in improvement in lung function or clinical symptoms between LAMA and LAMA/LABA.MethodsAmong 829 patients with COPD who were treated with LAMA or LAMA/LABA in our hospital, 112 patients (aged 40–89 years) matched the criteria. Of these 112 patients, 71 received LAMA (LAMA group) and 41 received LAMA/LABA (LAMA/LABA group) as the initial treatment. Various examination results such as lung function test values, symptom change, and frequency of exacerbations were compared between the two groups.ResultsCompared with the monotherapy, the combination therapy significantly improved the FEV1, inspiratory capacity (IC), and total COPD assessment test (CAT) scores. Comparing the improvement in each domain of the CAT produced by the combination therapy with that of the monotherapy, larger improvements were found for the domains of going out and sleeping. The frequency of exacerbations during the 24 weeks was significantly lower in the combination therapy group than in the LAMA monotherapy group (P=0.034). Although no relationship was found between improvement in FEV1 and any pretreatment factors in the LAMA/LABA group, the improvement in the CAT score was strongly related to the baseline CAT score, smoking index, and air trapping index (P-value <1×10−4).ConclusionIn this study of clinical practice, we found that LAMA/LABA combination therapy improved the clinical symptoms of COPD and IC and that the effects of the combination therapy were consistent with those observed in previous clinical trials.

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Genetic Control of Fatty Acid β-Oxidation in Chronic Obstructive Pulmonary Disease

Cited by 61 publications

References 47 publications

Transcriptional analysis identifies potential biomarkers and molecular regulators in pneumonia and COPD exacerbation

Transcriptional analysis identifies potential biomarkers and molecular regulators in pneumonia and COPD exacerbation

A functional SNP upstream of the <em>ADRB2</em> gene is associated with COPD

Effects of a single long-acting muscarinic antagonist agent and a long-acting muscarinic antagonist/long-acting β2-adrenoceptor agonist combination on lung function and symptoms in untreated COPD patients in Japan

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Genetic Control of Fatty Acid β-Oxidation in Chronic Obstructive Pulmonary Disease

Cited by 61 publications

References 47 publications

Transcriptional analysis identifies potential biomarkers and molecular regulators in pneumonia and COPD exacerbation

Transcriptional analysis identifies potential biomarkers and molecular regulators in pneumonia and COPD exacerbation

A functional SNP upstream of the <em>ADRB2</em> gene is associated with COPD

Effects of a single long-acting muscarinic antagonist agent and a long-acting muscarinic antagonist/long-acting &beta;2-adrenoceptor agonist combination on lung function and symptoms in untreated COPD patients in Japan

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Effects of a single long-acting muscarinic antagonist agent and a long-acting muscarinic antagonist/long-acting β2-adrenoceptor agonist combination on lung function and symptoms in untreated COPD patients in Japan