Array-based Comparative Genomic Hybridization (aCGH) Reveals Chromosomal Aberrations in Chronic Obstructive Pulmonary Disease (COPD):  A Preliminary Study

Chronic Obstructive Pulmonary Disease (COPD) is a complex disease with varying susceptibility. COPD development may be associated with copy number variation (CNV) in susceptible genomic regions. CNV also contributes to COPD heritability as these can cause changes in DNA fragment. CNVs in COPD smokers and COPD ex-smokers have not been examined so far. Thus, genome-wide array based comparative genomic hybridization (aCGH) was performed in COPD (n = 15) and control subjects (n = 13) to identify the vulnerable candidate genes for genetic susceptibility and CNVs in smoker (n = 6) and ex-smoker (n = 9) COPD and compare it with control subjects to identify the candidate genes potentially involved in the pathogenesis of COPD. Copy number gains and losses were detected in several chromosomal regions. Chromosomal regions found to be consistently associated with both subgroups of COPD, as well as, of control group were: 2p11.2, 4q13.2, 8p23.1, 8p11.22, 12p13.31 and 14q32.33. Chromosomal regions associated with COPD were 11p15.5, 15q11.1-q11.2 and Xq28, which had several genes, (viz., CHECK2P2, HERC2P3, GOLGA6L6 and GOLGA8CP) which were associated with COPD smokers, while several other genes (viz., LICAM, LCA10, AVPR2, GDI1, HOTS and H19) were found to be associated with COPD ex-smokers. These loci and genes may be explored further for their potential use as predictive markers and better understanding of pathophysiology of COPD.

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The role of gene polymorphisms in the pathogenesis of chronic obstructive pulmonary disease

Biologia ◽

10.2478/s11756-008-0020-4 ◽

2008 ◽

Vol 63 (1) ◽

Author(s):

Eva Slabá ◽

Pavol Joppa ◽

Ján Šalagovič ◽

Ružena Tkáčová

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Inflammatory Response ◽

Candidate Genes ◽

Pulmonary Disease ◽

Gene Polymorphisms ◽

Association Studies ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Positional Candidate ◽

Linkage Analyses

AbstractChronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. Irreversible airflow limitation, both progressive and associated with an inflammatory response of the lungs to noxious particles or gases, is a hallmark of the disease. Cigarette smoking is the most important environmental risk factor for COPD, nevertheless, only approximately 20–30% of smokers develop symptomatic disease. Epidemiological studies, case-control studies in relatives of patients with COPD, and twin studies suggest that COPD is a genetically complex disease with environmental factors and many involved genes interacting together. Two major strategies have been employed to identify the genes and the polymorphisms that likely contribute to the development of complex diseases: association studies and linkage analyses. Biologically plausible pathogenetic mechanisms are prerequisites to focus the search for genes of known function in association studies. Protease-antiprotease imbalance, generation of oxidative stress, and chronic inflammation are recognized as the principal mechanisms leading to irreversible airflow obstruction and parenchymal destruction in the lung. Therefore, genes which have been implicated in the pathogenesis of COPD are involved in antiproteolysis, antioxidant barrier and metabolism of xenobiotic substances, inflammatory response to cigarette smoke, airway hyperresponsiveness, and pulmonary vascular remodelling. Significant associations with COPD-related phenotypes have been reported for polymorphisms in genes coding for matrix metalloproteinases, microsomal epoxide hydrolase, glutathione-S-transferases, heme oxygenase, tumor necrosis factor, interleukines 1, 8, and 13, vitamin D-binding protein and β-2-adrenergic receptor (ADRB2), whereas adequately powered replication studies failed to confirm most of the previously observed associations. Genome-wide linkage analyses provide us with a novel tool to identify the general locations of COPD susceptibility genes, and should be followed by association analyses of positional candidate genes from COPD pathophysiology, positional candidate genes selected from gene expression studies, or dense single nucleotide polymorphism panels across regions of linkage. Haplotype analyses of genes with multiple polymorphic sites in linkage disequilibrium, such as the ADRB2 gene, provide another promising field that has yet to be explored in patients with COPD. In the present article we review the current knowledge about gene polymorphisms that have been recently linked to the risk of developing COPD and/or may account for variations in the disease course.

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Risk Factors for Postural and Functional Balance Impairment in Patients with Chronic Obstructive Pulmonary Disease

Journal of Clinical Medicine ◽

10.3390/jcm9020609 ◽

2020 ◽

Vol 9 (2) ◽

pp. 609

Author(s):

Jaekwan K. Park ◽

Nicolaas E. P. Deutz ◽

Clayton L. Cruthirds ◽

Sarah K. Kirschner ◽

Hangue Park ◽

...

Keyword(s):

Risk Factors ◽

Chronic Obstructive Pulmonary Disease ◽

Pulmonary Disease ◽

Postural Balance ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Balance Impairment ◽

Functional Balance ◽

Control Subjects ◽

Increased Risk

Reduced balance function has been observed during balance challenging conditions in the chronic obstructive pulmonary disease (COPD) population and is associated with an increased risk of falls. This study aimed to examine postural balance during quiet standing with eyes open and functional balance in a heterogeneous group of COPD and non-COPD (control) subjects, and to identify risk factors underlying balance impairment using a large panel of methods. In COPD and control subjects, who were mostly overweight and sedentary, postural and functional balance were assessed using center-of-pressure displacement in anterior-posterior (AP) and medio-lateral (ML) directions, and the Berg Balance Scale (BBS), respectively. COPD showed 23% greater AP sway velocity (p = 0.049). The presence of oxygen therapy, fat mass, reduced neurocognitive function, and the presence of (pre)diabetes explained 71% of the variation in postural balance in COPD. Transcutaneous oxygen saturation, a history of exacerbation, and gait speed explained 83% of the variation in functional balance in COPD. Neurocognitive dysfunction was the main risk factor for postural balance impairment in the control group. This suggests that specific phenotypes of COPD patients can be identified based on their type of balance impairment.

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Copy Number Variation of the Beta-Defensin Genes in Europeans: No Supporting Evidence for Association with Lung Function, Chronic Obstructive Pulmonary Disease or Asthma

PLoS ONE ◽

10.1371/journal.pone.0084192 ◽

2014 ◽

Vol 9 (1) ◽

pp. e84192 ◽

Cited By ~ 9

Author(s):

Louise V. Wain ◽

Linda Odenthal-Hesse ◽

Razan Abujaber ◽

Ian Sayers ◽

Caroline Beardsmore ◽

...

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Lung Function ◽

Copy Number Variation ◽

Pulmonary Disease ◽

Copy Number ◽

Chronic Obstructive ◽

Supporting Evidence ◽

Obstructive Pulmonary Disease ◽

Number Variation

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Muscle α-adrenergic responsiveness during exercise and ATP-induced vasodilation in chronic obstructive pulmonary disease patients

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00398.2017 ◽

2018 ◽

Vol 314 (2) ◽

pp. H180-H187 ◽

Cited By ~ 2

Author(s):

U. W. Iepsen ◽

G. W. Munch ◽

C. K. Ryrsø ◽

N. H. Secher ◽

P. Lange ◽

...

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Pulmonary Disease ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Control Subjects ◽

Matched Healthy Control ◽

Copd Patients ◽

Sympathetic Vasoconstriction ◽

Functional Sympatholysis ◽

Healthy Control

Sympathetic vasoconstriction is blunted in exercising muscle (functional sympatholysis) but becomes attenuated with age. We tested the hypothesis that functional sympatholysis is further impaired in chronic obstructive pulmonary disease (COPD) patients. We determined leg blood flow and calculated leg vascular conductance (LVC) during 1) femoral-arterial Tyramine infusion (evokes endogenous norepinephrine release, 1 µmol·min−1·kg leg mass−1), 2) one-legged knee extensor exercise with and without Tyramine infusion [10 W and 20% of maximal workload (WLmax)], 3) ATP (0.05 µmol·min−1·kg leg mass−1) and Tyramine infusion, and 4) incremental ATP infusions (0.05, 0.3, and 3.0 µmol·min−1·kg leg mass−1). We included 10 patients with moderate to severe COPD and 8 age-matched healthy control subjects. Overall, leg blood flow and LVC were lower in COPD patients during exercise ( P < 0.05). Tyramine reduced LVC in both groups at 10-W exercise (COPD: −3 ± 1 ml·min−1·mmHg−1and controls: −3 ± 1 ml·min−1·mmHg−1, P < 0.05) and 20% WLmax(COPD: −4 ± 1 ml·min−1·mmHg−1and controls: −3 ± 1 ml·min−1·mmHg−1, P < 0.05) with no difference between groups. Incremental ATP infusions induced dose-dependent vasodilation with no difference between groups, and, in addition, the vasoconstrictor response to Tyramine infused together with ATP was not different between groups (COPD: −0.03 ± 0.01 l·min−1·kg leg mass−1vs. controls: −0.04 ± 0.01 l·min−1·kg leg mass−1, P > 0.05). Compared with age-matched healthy control subjects, the vasodilatory response to ATP is intact in COPD patients and their ability to blunt sympathetic vasoconstriction (functional sympatholysis) as evaluated by intra-arterial Tyramine during exercise or ATP infusion is maintained.NEW & NOTEWORTHY The ability to blunt sympathetic vasoconstriction in exercising muscle and ATP-induced dilation in chronic obstructive pulmonary disease patients remains unexplored. Chronic obstructive pulmonary disease patients demonstrated similar sympathetic vasoconstriction in response to intra-arterial Tyramine during exercise and ATP-induced vasodilation compared with age-matched healthy control subjects.

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Patients with Chronic Obstructive Pulmonary Disease Walk with Altered Step Time and Step Width Variability as Compared with Healthy Control Subjects

Annals of the American Thoracic Society ◽

10.1513/annalsats.201607-547oc ◽

2017 ◽

Vol 14 (6) ◽

pp. 858-866 ◽

Cited By ~ 15

Author(s):

Jennifer M. Yentes ◽

Stephen I. Rennard ◽

Kendra K. Schmid ◽

Daniel Blanke ◽

Nicholas Stergiou

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Pulmonary Disease ◽

Chronic Obstructive ◽

Step Width ◽

Obstructive Pulmonary Disease ◽

Control Subjects ◽

Healthy Control

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Role of nitric oxide synthase/arginase balance in bronchial reactivity in patients with chronic obstructive pulmonary disease

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00109.2007 ◽

2008 ◽

Vol 294 (3) ◽

pp. L489-L497 ◽

Cited By ~ 18

Author(s):

Jean-Marc Tadié ◽

Priscilla Henno ◽

Ingrid Leroy ◽

Claire Danel ◽

Emmanuel Naline ◽

...

Keyword(s):

Nitric Oxide ◽

Chronic Obstructive Pulmonary Disease ◽

Pulmonary Disease ◽

Airflow Limitation ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Control Subjects ◽

Resting Tension ◽

Copd Patients ◽

Nos2 Expression

Competition between nitric oxide synthases (NOSs) and arginases for their common substrate l-arginine could be involved in the regulation of cholinergic airway reactivity and subsequent airway remodeling. The aims of this study were to evaluate the relationships between the expression of this enzymatic balance and the effects of NOS and arginase inhibition on bronchoconstrictive response to acetylcholine of patients without and with early chronic obstructive pulmonary disease (COPD). Twenty-two human bronchi [15 COPD (9 GOLD-0, 6 GOLD-1, -2-A), 7 nonsmokers] were investigated for immunohistochemistry and modulation of acetylcholine-induced airway constriction. Significantly increased expression of NOS2 in immunoblots of bronchial tissue and staining in smooth muscle cells was evidenced in patients with COPD compared with control subjects, whereas no modification of arginase expression was evidenced. Forced expiratory volume in 1 s (FEV1) and NOS2 expression were negatively correlated (ρ = −0.54, P = 0.027). Pharmacological experiments demonstrated that resting tension was elevated in COPD compared with control subjects (2,243 ± 154 vs. 1,574 ± 218 mg, P = 0.03) and was positively correlated with the expression of NOS2 (ρ = 0.61, P = 0.044), whereas constrictor response to acetylcholine was similar [active tension, sensitivity (−logEC10), and reactivity (slope)]. The sole effect of the specific arginase inhibitor Nω-hydroxy-nor-l-arginine (1 μM) was to decrease sensitivity in COPD patients, whereas 1 mM NG-nitro-l-arginine methyl ester unexpectedly decreased resting tension because of a non-cGMP-dependent effect. In conclusion, an upregulation of NOS2 expression in COPD patients is involved in airway tone regulation and functional airflow limitation, whereas increased arginase activity is involved in airway sensitivity.

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Relationship Between Circulating Serpina3g, Matrix Metalloproteinase-9, and Tissue Inhibitor of Metalloproteinase-1 and -2 with Chronic Obstructive Pulmonary Disease Severity

Biomolecules ◽

10.3390/biom9020062 ◽

2019 ◽

Vol 9 (2) ◽

pp. 62 ◽

Cited By ~ 2

Author(s):

Pelin Uysal ◽

Hafize Uzun

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Matrix Metalloproteinase ◽

Pulmonary Disease ◽

Tissue Inhibitor Of Metalloproteinase ◽

Chronic Obstructive ◽

Tissue Inhibitor ◽

Obstructive Pulmonary Disease ◽

Control Subjects ◽

Copd Patients ◽

Metalloproteinase 9

Chronic obstructive pulmonary disease (COPD) is influenced by genetic and environmental factors. A protease-antiprotease imbalance has been suggested as a possible pathogenic mechanism for COPD. Here, we examined the relationship between circulating serpina3g, matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinase-1 and -2 (TIMP-1 and -2, respectively) and severity of COPD. We included 150 stable COPD patients and 35 control subjects in the study. The COPD patients were classified into four groups (I, II, III, and IV), according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines based on the severity of symptoms and the exacerbation risk. Plasma serpina3g, MMP-9, and TIMP-1 and -2 concentrations were significantly higher in the all patients than in control subjects. Plasma serpina3g, MMP-9, and TIMP-1 and -2 concentrations were significantly higher in groups III and IV than in groups I and II. A negative correlation between serpina3g, MMP-9, and TIMP-1 and -2 levels and the forced expiratory volume in 1 s (FEV1) was observed. MMP-9 concentration and the MMP-9/TIMP-1 ratio were higher in patients with emphysema than in other phenotypes (both with p < 0.01). The findings of this study suggest that circulating serpina3g, MMP-9, and TIMP-1 and -2 levels may play an important role in airway remodeling in COPD pathogenesis. Disrupted protease-antiprotease imbalance in patients with COPD is related to the presence of airway injury. MMP-9 concentration and the MMP-9/TIMP-1 ratio are the best predictors of emphysema in COPD patients.

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