scholarly journals Elevated plasma level of Pentraxin 3 is associated with emphysema and mortality in smokers

Thorax ◽  
2021 ◽  
pp. thoraxjnl-2020-215356
Author(s):  
Yingze Zhang ◽  
John Tedrow ◽  
Mehdi Nouraie ◽  
Xiaoyun Li ◽  
Divay Chandra ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hyaluronic Acid ◽  
Lung Tissue ◽  
Regulatory Gene ◽  
Airflow Obstruction ◽  
Chronic Obstructive ◽  
Pentraxin 3 ◽  
Tobacco Exposure ◽  
Regulatory Variants ◽  
Emphysema Severity

BackgroundPentraxin 3 (PTX3) influences innate immunity and inflammation, host defence, the complement cascade and angiogenesis. PTX3 expression in lung and blood of subjects with tobacco exposure, and its potential relationship with disease pattern and clinical outcome are poorly understood.MethodsUsing independent platforms and cohorts, we identified associations of PTX3 gene expression in lung tissue and plasma from current and former tobacco smokers (with and without chronic obstructive pulmonary disease, COPD) to disease phenotypes including quantitative CT determined emphysema, lung function, symptoms and survival. Two putative regulatory variants of the PTX3 gene were examined for association with COPD manifestations. The relationship between plasma PTX3 and hyaluronic acid levels was further examined.ResultsPTX3 gene expression in lung tissue was directly correlated with emphysema severity (p<0.0001). Circulating levels of PTX3 were inversely correlated with FEV1 (p=0.006), and positively associated with emphysema severity (p=0.004) and mortality (p=0.008). Two PTX3 gene regulatory variants were associated with a lower risk for emphysema and expiratory airflow obstruction, and plasma levels of PTX3 and hyaluronic acid were related.ConclusionsThese data show strong and overlapping associations of lung and blood PTX3 levels, and PTX3 regulatory gene variants, with the severity of airflow obstruction, emphysema and mortality among smokers. These findings have potential implications regarding the pathogenesis of smoking-related lung diseases and warrant further exploration for the use of PTX3 as a predictive biomarker.

scholarly journals Genetic regulation of gene expression of MIF family members in lung tissue

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Laura Florez-Sampedro ◽  
Corry-Anke Brandsma ◽  
Maaike de Vries ◽  
Wim Timens ◽  
Rene Bults ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Tissue ◽  
Splice Variants ◽  
Genetic Regulation ◽  
Regulation Of Gene Expression ◽  
Chronic Obstructive ◽  
Nucleotide Polymorphisms ◽  
Related Factors ◽  
Dopachrome Tautomerase ◽  
Copd Patients

Abstract Macrophage migration inhibitory factor (MIF) is a cytokine found to be associated with chronic obstructive pulmonary disease (COPD). However, there is no consensus on how MIF levels differ in COPD compared to control conditions and there are no reports on MIF expression in lung tissue. Here we studied gene expression of members of the MIF family MIF, D-Dopachrome Tautomerase (DDT) and DDT-like (DDTL) in a lung tissue dataset with 1087 subjects and identified single nucleotide polymorphisms (SNPs) regulating their gene expression. We found higher MIF and DDT expression in COPD patients compared to non-COPD subjects and found 71 SNPs significantly influencing gene expression of MIF and DDTL. Furthermore, the platform used to measure MIF (microarray or RNAseq) was found to influence the splice variants detected and subsequently the direction of the SNP effects on MIF expression. Among the SNPs found to regulate MIF expression, the major LD block identified was linked to rs5844572, a SNP previously found to be associated with lower diffusion capacity in COPD. This suggests that MIF may be contributing to the pathogenesis of COPD, as SNPs that influence MIF expression are also associated with symptoms of COPD. Our study shows that MIF levels are affected not only by disease but also by genetic diversity (i.e. SNPs). Since none of our significant eSNPs for MIF or DDTL have been described in GWAS for COPD or lung function, MIF expression in COPD patients is more likely a consequence of disease-related factors rather than a cause of the disease.

scholarly journals Evaluation of Selected IL6/STAT3 Pathway Molecules and miRNA Expression in Chronic Obstructive Pulmonary Disease - the Search for New Diagnostic Markers

2021 ◽  
Author(s):  
Justyna Kiszałkiewicz ◽  
Sebastian Majewski ◽  
Wojciech J. Piotrowski ◽  
Paweł Górski ◽  
Dorota Pastuszak-Lewandoska ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mirna Expression ◽  
Smoking Status ◽  
Control Group ◽  
Chronic Obstructive ◽  
Tobacco Exposure ◽  
Expression Levels ◽  
Stat3 Pathway ◽  
Global Epidemic ◽  
Gene Expression Levels

Abstract Background COPD has been regarded as a global epidemic due to an increase in pollution and tobacco exposure. Therefore, the study of molecular mechanism as the basis for modern therapy is important. Objective The aim of the study was the assessment of gene expression levels, IL-6, IL-6ST, PIAS3, STAT3, and miRNAs, miR-1, miR-106b, miR-155, in patients with COPD. Methods Induced sputum as well as PBMC were collected from 40 patients clinically verified according to the GOLD 2017 (A-D) classification and from the control group (n = 20). The levels of gene and miRNA expression were analysed by qPCR. Results Statistically significant differences between the study group vs. control group were observed for IL-6 (P = 0.008, Mann-Whitney U test), and miR-155 (P = 0.03, Mann-Whitney U test). There were statistically significant differences between patients: current smokers vs. ex- smokers for STAT3, (P = 0.04, Mann-Whitney U test) and miR-155 (P = 0.03, Mann-Whitney U test) with a higher expression in current smokers. Conclusions Differences in gene expression levels of the IL-6 / gp130 / STAT3 pathway and miRNA depending on the smoking status and classification of patients according to GOLD suggest the importance of these genes in the pathogenesis of COPD and may indicate their potential utility in monitoring the course of the disease.

scholarly journals Protective effect of club cell secretory protein (CC-16) on COPD risk and progression: a Mendelian randomisation study

Thorax ◽  
2020 ◽  
Vol 75 (11) ◽  
pp. 934-943
Author(s):  
Stephen Milne ◽  
Xuan Li ◽  
Ana I Hernandez Cordero ◽  
Chen Xi Yang ◽  
Michael H Cho ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Tissue ◽  
Causal Effect ◽  
Secretory Protein ◽  
Health Study ◽  
Mendelian Randomisation ◽  
Chronic Obstructive ◽  
Quantitative Trait Locus Study ◽  
Club Cell ◽  
A Genome

BackgroundThe anti-inflammatory pneumoprotein club cell secretory protein-16 (CC-16) is associated with the clinical expression of chronic obstructive pulmonary disease (COPD). We aimed to determine if there is a causal effect of serum CC-16 level on the risk of having COPD and/or its progression using Mendelian randomisation (MR) analysis.MethodsWe performed a genome-wide association meta-analysis for serum CC-16 in two COPD cohorts (Lung Health Study (LHS), n=3850 and ECLIPSE, n=1702). We then used the CC-16-associated single-nucleotide polymorphisms (SNPs) as instrumental variables in MR analysis to identify a causal effect of serum CC-16 on ‘COPD risk’ (ie, case status in the International COPD Genetics Consortium/UK-Biobank dataset; n=35 735 COPD cases, n=222 076 controls) and ‘COPD progression’ (ie, annual change in forced expiratory volume in 1 s in LHS and ECLIPSE). We also determined the associations between SNPs associated with CC-16 and gene expression using n=1111 lung tissue samples from the Lung Expression Quantitative Trait Locus Study.ResultsWe identified seven SNPs independently associated (p<5×10–8) with serum CC-16 levels; six of these were novel. MR analysis suggested a protective causal effect of increased serum CC-16 on COPD risk (MR estimate (SE) −0.11 (0.04), p=0.008) and progression (LHS only, MR estimate (SE) 7.40 (3.28), p=0.02). Five of the SNPs were also associated with gene expression in lung tissue (at false discovery rate <0.1) of several genes, including the CC-16-encoding gene SCGB1A1.ConclusionWe have identified several novel genetic variants associated with serum CC-16 level in COPD cohorts. These genetic associations suggest a potential causal effect of serum CC-16 on the risk of having COPD and its progression, the biological basis of which warrants further investigation.

Evidence of altered brain regulatory gene expression in tobacco-exposed fetuses

2017 ◽  
Vol 45 (9) ◽  
Author(s):  
Hamisu M. Salihu ◽  
Arnut Paothong ◽  
Rachita Das ◽  
Lindsey M. King ◽  
Anupam Pradhan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Smoking Status ◽  
Quantitative Polymerase Chain Reaction ◽  
Regulatory Gene ◽  
Fetal Brain ◽  
Preliminary Evidence ◽  
Regulatory Genes ◽  
Prenatal Smoking ◽  
Tobacco Exposure ◽  
Salivary Cotinine

AbstractAim:We sought to determine the association between prenatal smoking status and expression of fetal brain regulatory genes.Methods:At delivery, we collected information from parturient women on prenatal smoking habits and analyzed salivary cotinine levels. We obtained neonatal umbilical cord blood and extracted total RNA. We then employed the quantitative polymerase chain reaction (QPCR) analyses and the comparative CT method to calculate the relative gene expression of selected fetal brain regulatory genes responsible for (1) brain growth (brain-derived neutrotrophic factor, BDNF), (2) myelination (proteolipidic protein 1, PLP1 and myelin basic protein, MBP), and (3) neuronal migration and cell-cell interactions during fetal brain development or RLN. The χResults:Of the 39 maternal-infant dyads included in this study, 25.6% were non-smokers, 43.6% were passive smokers and 30.8% were active smokers. The results showed down-regulation of the selected fetal brain regulatory genes among active smokers.Conclusions:These findings represent preliminary evidence in humans that intrauterine tobacco exposure impacts fetal brain programming. Future studies are warranted to examine whether our findings represent potential mechanisms through which adverse childhood/adult-onset cognitive and behavioral outcomes that have been previously linked to intrauterine exposure occur.

scholarly journals Deregulated Stat3 signaling dissociates pulmonary inflammation from emphysema in gp130 mutant mice

2012 ◽  
Vol 302 (7) ◽  
pp. L627-L639 ◽  
Author(s):  
Saleela M. Ruwanpura ◽  
Louise McLeod ◽  
Alistair Miller ◽  
Jessica Jones ◽  
Ross Vlahos ◽  
...  
Keyword(s):  
Lung Tissue ◽  
Lung Inflammation ◽  
Human Lung ◽  
Pulmonary Inflammation ◽  
Airflow Obstruction ◽  
Chronic Obstructive ◽  
Alveolar Cells ◽  
Human Lung Tissue ◽  
Stat3 Signaling

Interleukin (IL)-6 is a potent immunomodulatory cytokine that is associated with emphysema, a major component of chronic obstructive pulmonary disease (COPD). IL-6 signaling via the gp130 coreceptor is coupled to multiple signaling pathways, especially the latent transcription factor signal transducer and activator of transcription (Stat)3. However, the pathological role of endogenous gp130-dependent Stat3 activation in emphysema is ill defined. To elucidate the role of the IL-6/gp130/Stat3 signaling axis in the cellular and molecular pathogenesis of emphysema, we employed a genetic complementation strategy using emphysematous gp130F/F mice displaying hyperactivation of endogenous Stat3 that were interbred with mice to impede Stat3 activity. Resected human lung tissue from patients with COPD and COPD-free individuals was also evaluated by immunohistochemistry. Genetic reduction of Stat3 hyperactivity in gp130F/F: Stat3 −/+ mice prevented lung inflammation and excessive protease activity; however, emphysema still developed. In support of these findings, Stat3 activation levels in human lung tissue correlated with the extent of pulmonary inflammation but not airflow obstruction in COPD. Furthermore, COPD lung tissue displayed increased levels of IL-6 and apoptotic alveolar cells, supporting our previous observation that increased endogenous IL-6 expression in the lungs of gp130F/F mice contributes to emphysema by promoting alveolar cell apoptosis. Collectively, our data suggest that IL-6 promotes emphysema via upregulation of Stat3-independent apoptosis, whereas IL-6 induction of lung inflammation occurs via Stat3. We propose that while discrete targeting of Stat3 may alleviate pulmonary inflammation, global targeting of IL-6 potentially represents a therapeutically advantageous approach to combat COPD phenotypes where emphysema predominates.

scholarly journals Common genes underlying asthma and COPD? Genome-wide analysis on the Dutch hypothesis

2014 ◽  
Vol 44 (4) ◽  
pp. 860-872 ◽  
Author(s):  
Joanna Smolonska ◽  
Gerard H. Koppelman ◽  
Cisca Wijmenga ◽  
Judith M. Vonk ◽  
Pieter Zanen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Tissue ◽  
Blood Cells ◽  
Association Studies ◽  
Chronic Obstructive ◽  
Eqtl Analysis ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Replication Phase ◽  
Genome Wide Significance

Asthma and chronic obstructive pulmonary disease (COPD) are thought to share a genetic background (“Dutch hypothesis”).We investigated whether asthma and COPD have common underlying genetic factors, performing genome-wide association studies for both asthma and COPD and combining the results in meta-analyses.Three loci showed potential involvement in both diseases: chr2p24.3, chr5q23.1 and chr13q14.2, containing DDX1, COMMD10 (both participating in the nuclear factor (NF) κβ pathway) and GNG5P5, respectively. Single nucleotide polymorphisms (SNPs) rs9534578 in GNG5P5 reached genome-wide significance after first replication phase (p=9.96×10−9). The second replication phase, in seven independent cohorts, provided no significant replication. Expression quantitative trait loci (eQTL) analysis in blood cells and lung tissue on the top 20 associated SNPs identified two SNPs in COMMD10 that influenced gene expression.Inflammatory processes differ in asthma and COPD and are mediated by NF-κβ, which could be driven by the same underlying genes, COMMD10 and DDX1. None of the SNPs reached genome-wide significance. Our eQTL studies support a functional role for two COMMD10 SNPs, since they influence gene expression in both blood cells and lung tissue. Our findings suggest that there is either no common genetic component in asthma and COPD or, alternatively, different environmental factors, e.g. lifestyle and occupation in different countries and continents, which may have obscured the genetic common contribution.

scholarly journals Pentraxin 3: A Novel Biomarker for Inflammatory Cardiovascular Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Kenji Inoue ◽  
Tatsuhiko Kodama ◽  
Hiroyuki Daida
Keyword(s):  
Gene Expression ◽  
Cardiovascular Disease ◽  
Pentraxin 3 ◽  
Human Endothelial Cells ◽  
C Reactive Protein ◽  
Physiological Concentration ◽  
Reactive Protein ◽  
Atherosclerotic Lesions ◽  
Human Genes

Numerous studies have recently examined the role of pentraxin 3 (PTX3) in clinical situations. The pentraxin family includes C-reactive protein (CRP); however, unlike CRP, PTX3 is expressed predominantly in atherosclerotic lesions that involve macrophages, neutrophils, dendritic cells, or smooth muscle cells. Interestingly, PTX3 gene expression in human endothelial cells is suppressed to a greater extent by pitavastatin than the expression of 6,000 other human genes that have been examined, suggesting that PTX3 may be a novel biomarker for inflammatory cardiovascular disease. The expression and involvement of PTX3 in cardiovascular diseases are discussed in this paper, along with the characteristics of PTX3 that make it a suitable biomarker; namely, that the physiological concentration is known and it is independent of other risk factors. The results discussed in this paper suggest that further investigations into the potential novel use of PTX3 as a biomarker for inflammatory cardiovascular disease should be undertaken.

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