scholarly journals Pre-adolescence DNA methylation is associated with lung function trajectories from pre-adolescence to adulthood

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Shadia Khan Sunny ◽  
Hongmei Zhang ◽  
Fawaz Mzayek ◽  
Caroline L. Relton ◽  
Susan Ring ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Lung Function ◽  
Lung Diseases ◽  
Critical Role ◽  
Enrichment Analysis ◽  
Chronic Obstructive ◽  
Chronic Lung Diseases ◽  
Parents And Children ◽  
Males And Females

Abstract Background The pattern of lung function development from pre-adolescence to adulthood plays a significant role in the pathogenesis of respiratory diseases. Inconsistent findings in genetic studies on lung function trajectories, the importance of DNA methylation (DNA-M), and the critical role of adolescence in lung function development motivated the present study of pre-adolescent DNA-M with lung function trajectories. This study investigated epigenome-wide associations of DNA-M at cytosine-phosphate-guanine dinucleotide sites (CpGs) at childhood with lung function trajectories from childhood to young adulthood. Methods DNA-M was measured in peripheral blood at age 10 years in the Isle of Wight (IOW) birth cohort. Spirometry was conducted at ages 10, 18, and 26 years. A training/testing-based method was used to screen CpGs. Multivariable logistic regressions were applied to assess the association of DNA-M with lung function trajectories from pre-adolescence to adulthood. To detect differentially methylated regions (DMRs) among CpGs, DMR enrichment analysis was conducted. Findings were further tested in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Pathway analyses were performed on the mapped genes of the identified CpGs and DMRs. Biological relevance of the identified CpGs was assessed with gene expression. All analyses were stratified by sex. Results High and low trajectories of FVC, FEV1, and FEV1/FVC in each sex were identified. At PBonferroni < 0.05, DNA-M at 96 distinct CpGs (41 in males) showed associations with FVC, FEV1, and FEV1/FVC trajectories in IOW cohort. These 95 CpGs (cg24000797 was disqualified) were further tested in ALSPAC; 44 CpGs (19 in males) of these 95 showed the same directions of association as in the IOW cohort; and three CpGs (two in males) were replicated. DNA-M at two and four CpGs showed significant associations with the corresponding gene expression in males and females, respectively. At PFDR < 0.05, 23 and 10 DMRs were identified in males and females, respectively. Pathways were identified; some of those were linked to lung function and chronic obstructive lung diseases. Conclusion The identified CpGs at pre-adolescence have the potential to serve as candidate markers for lung function trajectory prediction and chronic lung diseases.

scholarly journals Sex-specific longitudinal association of DNA methylation with lung function

2021 ◽  
pp. 00127-2021
Author(s):  
Shadia Khan Sunny ◽  
Hongmei Zhang ◽  
Caroline L. Relton ◽  
Susan Ring ◽  
Latha Kadalayil ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Function ◽  
Mixed Models ◽  
Enrichment Analysis ◽  
Expression Data ◽  
Specific Effects ◽  
Parents And Children ◽  
Longitudinal Association ◽  
Males And Females ◽  
Avon Longitudinal Study

Investigating whether DNA-M at an earlier age is associated with lung function at a later age and whether this relationship differs by sex could enable prediction of future lung function deficit.A training/testing-based technique was used to screen 402 714 cytosine-phosphate-guanine dinucleotide sites (CpGs) to assess the longitudinal association of blood-based DNA-M at ages 10 and 18-years with lung function at 18 and 26-years, respectively, in the Isle of Wight birth cohort (IOWBC). Multivariable linear mixed models were applied to the CpGs that passed screening. To detect differentially methylated regions (DMRs), DMR enrichment analysis was conducted. Findings were further examined in the Avon Longitudinal Study of Parents and Children (ALSPAC). Biological relevance of the identified CpGs was assessed utilizing gene expression data.DNA-M at 8 CpGs (FEV1: 5 and FEV1/FVC: 3 CpGs) at an earlier age was associated with lung function at a later age regardless of sex, while at 13 CpGs (FVC: 5, FEV1:3, and FEV1/FVC: 5 CpGs), the associations were sex-specific (pFDR<0.05) in IOWBC with consistent directions of association in ALSPAC (IOWBC-ALSPAC consistent CpGs). cg16582803 (WNT10A) and cg14083603 (ZGPAT) were replicated in ALSPAC for main and sex-specific effects, respectively. Among IOWBC-ALSPAC consistent CpGs, DNA-M at cg01376079 (SSH3) and cg07557690 (TGFBR3) was associated with gene expression both longitudinally and cross-sectionally. In total, 57 and 170 DMRs were linked to lung function longitudinally in males and females, respectively.CpGs showing longitudinal associations with lung function have the potential to serve as candidate markers in future studies on lung function deficit prediction.

scholarly journals DNA methylation at birth is associated with lung function development till age 26 years

2020 ◽  
pp. 2003505
Author(s):  
Nandini Mukherjee ◽  
Ryan Arathimos ◽  
Su Chen ◽  
Parnian Kheirkhah Rahimabad ◽  
Luhang Han ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Lung Function ◽  
Early Adulthood ◽  
Forced Expiratory Volume ◽  
Parents And Children ◽  
Forced Expiratory Flow ◽  
Heel Prick ◽  
F2 Generation ◽  
Preventative Interventions

Little is known about whether DNA methylation (DNAm) of cytosine-phosphate-guanine (CpG) sites at birth predicts patterns of lung function development. We used heel prick DNAm from the F1-generation of Isle of Wight birth cohort (IOWBC-F1) for discovery of CpGs associated with lung function trajectories (Forced Expiratory Volume, Forced Vital Capacity, their ratio, and Forced Expiratory Flow at 25–75%) over the first 26 years, stratified by sex. We replicated the findings in the Avon Longitudinal Study of Parents and Children (ALSPAC) using cord blood DNAm.Epigenome-wide screening was applied to identify CpGs associated with lung function trajectories in 396 boys, and 390 girls of IOWBC-F1. Replication in ALSPAC focused on lung function at ages 8, 15 and 24 years. Statistically significantly replicated CpGs were investigated for consistency in direction of association between cohorts, stability of DNAm over time in IOWBC-F1, relevant biological processes, and for association with gene expression (n=161) in IOWBC F2-generation (IOWBC-F2).Differential DNAm of 8 CpGs on genes GLUL, MYCN, HLX, LHX1, COBL, COL18A1, STRA6, and WNT11 involved in developmental processes, were significantly associated with lung function in the same direction in IOWBC-F1 and ALSPAC, and showed stable patterns at birth, age 10 and 18 years between high and low lung function trajectories in IOWBC-F1. CpGs on LHX1 and COL18A1 were linked to gene expression in IOWBC-F2.In two large cohorts, novel DNAm at birth were associated with patterns of lung function in adolescence and early adulthood providing possible targets for preventative interventions against adverse pulmonary function development.

Lung Function and Quality of Life in Workers with Chemical and Dust Exposure

2018 ◽  
Vol 69 (2) ◽  
pp. 346-349 ◽  
Author(s):  
Marina Ruxandra Otelea ◽  
Oana Cristina Arghir ◽  
Corina Zugravu ◽  
Eugenia Naghi ◽  
Sabina Antoniu ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Occupational Exposure ◽  
Lung Function ◽  
Lung Diseases ◽  
Dust Exposure ◽  
Chronic Lung Diseases ◽  
Respiratory Exposure ◽  
Increased Risk ◽  
Occupational Settings

Regarding the widely distribution of respiratory exposure hazards in occupational settings, workers have an increased risk for chronic lung diseases. For assessing the quality of life and lung function in workers exposed to chemicals and dust, St George�s Respiratory Questionnaire (SGRQ) and spirometry were performed among 40 patients, admitted in Occupational Clinic Department of Colentina Hospital, Bucharest, Romania, during February, 2017. SGRQ showed different predictors for patients according to their occupational exposure and total symptoms score correlated better with decreased spirometric parameters in defining lung function deterioration. Quality of life is earlier affected than lung function deterioration and emphasises the need of more sensitive methods for an earlier identification and better evaluation of respiratory hazards in different workplaces.

scholarly journals Epigenome-wide association study of whole blood gene expression in Framingham Heart Study participants provides molecular insight into the potential role of CHRNA5 in cigarette smoking-related lung diseases

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Chen Yao ◽  
Roby Joehanes ◽  
Rory Wilson ◽  
Toshiko Tanaka ◽  
Luigi Ferrucci ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Dna Methylation ◽  
Cigarette Smoking ◽  
Association Study ◽  
Whole Blood ◽  
Lung Diseases ◽  
Epigenetic Modification ◽  
Blood Gene Expression ◽  
Increased Risk

Abstract Background DNA methylation is a key epigenetic modification that can directly affect gene regulation. DNA methylation is highly influenced by environmental factors such as cigarette smoking, which is causally related to chronic obstructive pulmonary disease (COPD) and lung cancer. To date, there have been few large-scale, combined analyses of DNA methylation and gene expression and their interrelations with lung diseases. Results We performed an epigenome-wide association study of whole blood gene expression in ~ 6000 individuals from four cohorts. We discovered and replicated numerous CpGs associated with the expression of cis genes within 500 kb of each CpG, with 148 to 1,741 cis CpG-transcript pairs identified across cohorts. We found that the closer a CpG resided to a transcription start site, the larger its effect size, and that 36% of cis CpG-transcript pairs share the same causal genetic variant. Mendelian randomization analyses revealed that hypomethylation and lower expression of CHRNA5, which encodes a smoking-related nicotinic receptor, are causally linked to increased risk of COPD and lung cancer. This putatively causal relationship was further validated in lung tissue data. Conclusions Our results provide a large and comprehensive association study of whole blood DNA methylation with gene expression. Expression platform differences rather than population differences are critical to the replication of cis CpG-transcript pairs. The low reproducibility of trans CpG-transcript pairs suggests that DNA methylation regulates nearby rather than remote gene expression. The putatively causal roles of methylation and expression of CHRNA5 in relation to COPD and lung cancer provide evidence for a mechanistic link between patterns of smoking-related epigenetic variation and lung diseases, and highlight potential therapeutic targets for lung diseases and smoking cessation.

scholarly journals Newborn DNA-methylation, childhood lung function, and the risks of asthma and COPD across the life course

2019 ◽  
Vol 53 (4) ◽  
pp. 1801795 ◽  
Author(s):  
Herman T. den Dekker ◽  
Kimberley Burrows ◽  
Janine F. Felix ◽  
Lucas A. Salas ◽  
Ivana Nedeljkovic ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Function ◽  
Life Course ◽  
Cord Blood ◽  
Childhood Asthma ◽  
Respiratory Health ◽  
Forced Expiratory Volume ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
The Life Course

RationaleWe aimed to identify differentially methylated regions (DMRs) in cord blood DNA associated with childhood lung function, asthma and chronic obstructive pulmonary disease (COPD) across the life course.MethodsWe meta-analysed epigenome-wide data of 1688 children from five cohorts to identify cord blood DMRs and their annotated genes, in relation to forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity (FVC) ratio and forced expiratory flow at 75% of FVC at ages 7–13 years. Identified DMRs were explored for associations with childhood asthma, adult lung function and COPD, gene expression and involvement in biological processes.ResultsWe identified 59 DMRs associated with childhood lung function, of which 18 were associated with childhood asthma and nine with COPD in adulthood. Genes annotated to the top 10 identified DMRs were HOXA5, PAOX, LINC00602, ABCA7, PER3, CLCA1, VENTX, NUDT12, PTPRN2 and TCL1A. Differential gene expression in blood was observed for 32 DMRs in childhood and 18 in adulthood. Genes related with 16 identified DMRs were associated with respiratory developmental or pathogenic pathways.InterpretationOur findings suggest that the epigenetic status of the newborn affects respiratory health and disease across the life course.

scholarly journals Chronic Obstructive Pulmonary Disease: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases

2014 ◽  
Vol 11 (Supplement 3) ◽  
pp. S154-S160 ◽  
Author(s):  
M. Bradley Drummond ◽  
A. Sonia Buist ◽  
James D. Crapo ◽  
Robert A. Wise ◽  
Stephen I. Rennard
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Primary Prevention ◽  
Pulmonary Disease ◽  
Lung Diseases ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Chronic Lung Diseases

scholarly journals THE MICROBIOTA OF LOWER AIRWAYS IN PATIENTS WITH CHRONIC OBSTRUCTIVE LUNG DISEASES

2018 ◽  
pp. 53-60
Author(s):  
S. A. Mazurina ◽  
G. A. Danilina ◽  
M. Yu. Smirnova ◽  
G. L. Osipova ◽  
V. B. Gervazieva ◽  
...  
Keyword(s):  
Burkholderia Cepacia ◽  
Lung Diseases ◽  
Morphological Changes ◽  
Bacterial Species ◽  
Chronic Obstructive Lung Disease ◽  
Induced Sputum ◽  
Chronic Obstructive ◽  
Obstructive Lung Diseases ◽  
Chronic Lung Diseases ◽  
Detection Frequency

Aim. We aimed to estimate the composition and the detection frequency of bacterial species in induced sputum samples from patients with bronchial asthma (BA), chronic obstructive lung disease (COPD) and its combined phenotype (ACOS). Materials and methods. Bacteriological examination of samples of induced sputum in patients with chronic obstructive pulmonary diseases (BA, COPD) was carried out. Results. Patients with asthma-COPD overlap syndrome exhibit more diverse bacterial species composition as represented both by gram-positive Streptococcus sрp., Staphylococcus spр., gram-negative Klebsiella pneumoniaе, Escherichia coli, Serratia marcescens, Pseudomonas aeruginosa, Haemophilus influenzae, Burkholderia cepacia and rodlike bacterium Corynebacterium spр., Actinomyces spр. и Tsukamurella рaurometabola as compared to patients with only one diagnosis of COPD or asthma. In addition, we revealed the differences between microbiological diversity and predominance of Streptococcus spр, Neisseria subflava with decrease of Enterococcus sрр. in samples from patients with complicated forms of obstructive lung diseases as COPD and ACOS, with pulmonary emphysema and/or pneumosclerosis. Conclusion. The biodiversity of lung microbiome could be one of the pathology risk factors in patients with chronic lung diseases, on the other hand reflecting the structural morphological changes in the lung tissue as a result of sustainable inflammation.

scholarly journals Nonantibiotic macrolides restore airway macrophage phagocytic function with potential anti-inflammatory effects in chronic lung diseases

2017 ◽  
Vol 312 (5) ◽  
pp. L678-L687 ◽  
Author(s):  
Sandra Hodge ◽  
Hai B. Tran ◽  
Rhys Hamon ◽  
Eugene Roscioli ◽  
Greg Hodge ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Lung Diseases ◽  
Bacterial Resistance ◽  
Scavenger Receptor ◽  
Lower Airway ◽  
Chronic Obstructive ◽  
Apoptotic Cells ◽  
Nontypeable Haemophilus Influenzae ◽  
Pyrin Domain ◽  
Chronic Lung Diseases

We reported defective efferocytosis associated with cigarette smoking and/or airway inflammation in chronic lung diseases, including chronic obstructive pulmonary disease, severe asthma, and childhood bronchiectasis. We also showed defects in phagocytosis of nontypeable Haemophilus influenzae (NTHi), a common colonizer of the lower airway in these diseases. These defects could be substantially overcome with low-dose azithromycin; however, chronic use may induce bacterial resistance. The aim of the present study was therefore to investigate two novel macrolides—2′-desoxy-9-(S)-erythromycylamine (GS-459755) and azithromycin-based 2′-desoxy molecule (GS-560660)—with significantly diminished antibiotic activity against Staphylococcus aureus, Streptococcus pneumonia, Moraxella catarrhalis, and H. influenzae. We tested their effects on efferocytosis, phagocytosis of NTHi, cell viability, receptors involved in recognition of apoptotic cells and/or NTHi (flow cytometry), secreted and cleaved intracellular IL-1β (cytometric bead array, immunofluorescence/confocal microscopy), and nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) using primary alveolar macrophages and THP-1 macrophages ± 10% cigarette smoke extract. Dose-response experiments showed optimal prophagocytic effects of GS-459755 and GS-560660 at concentrations of 0.5–1 µg/ml compared with our findings with azithromycin. Both macrolides significantly improved phagocytosis of apoptotic cells and NTHi (e.g., increases in efferocytosis and phagocytosis of NTHi: GS-459755, 23 and 22.5%, P = 0.043; GS-560660, 23.5 and 22%, P = 0.043, respectively). Macrophage viability remained >85% following 24 h exposure to either macrolide at concentrations up to 20 µg/ml. Secreted and intracellular-cleaved IL-1β was decreased with both macrolides with no significant changes in recognition molecules c-mer proto-oncogene tyrosine kinase; scavenger receptor class A, member 1; Toll-like receptor 2/4; or CD36. Particulate cytoplasmic immunofluorescence of NLRP3 inflammasome was also reduced significantly. We conclude that GS-459755 and GS-560660 may be useful for reducing airway inflammation in chronic lung diseases without inducing bacterial resistance.

824 Case Series on the Use of Volume Assured Pressure Support in Patients with Chronic Pulmonary Disease and Progressive Hypercapnia

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A321-A322
Author(s):  
William LeMaster ◽  
Dale Jun ◽  
Sharon De Cruz ◽  
Michelle Zeidler ◽  
Rajan Saggar
Keyword(s):  
Respiratory Failure ◽  
Lung Disease ◽  
Pulmonary Disease ◽  
Lung Diseases ◽  
Lung Transplant ◽  
Pressure Support ◽  
Case Series ◽  
Chronic Obstructive ◽  
Hypoxemic Respiratory Failure ◽  
Chronic Lung Diseases

Abstract Introduction Chronic hypercapnia results from destruction of lung parenchyma which occurs in chronic lung diseases including interstitial lung disease (ILD), bronchiectasis, and chronic lung transplant rejection. Many patients with these diseases will experience progressive respiratory failure eventually requiring consideration of transplantation or re-transplantation. Due to physiologic changes in sleep including reduction in tidal volume, worsening air tapping, and REM atonia, hypoventilation can be exacerbated during the sleeping hours. We present four patients who were prescribed nocturnal Volume Assured Pressure Support VAPS for their progressive hypercapnia. Report of case(s) Subject 1 is a 72 year old female with severe bronchiectasis and restrictive lung disease due to TB pneumonia at a young age. Subject 2 is a 45 year old male with history of pulmonary cavitation due to extensive TB disease when he was younger. Subject 3 is a 45-year-old woman with rheumatoid arthritis related ILD with associated pulmonary arterial hypertension. Subject 4 is a 74 year old patient with a bilateral lung transplant for IPF complicated by bronchiolitis obliterans syndrome who presented with progressive dyspnea and hypercapnia. Despite optimal therapy, all of these patients were admitted for hypercapnic and hypoxemic respiratory failure requiring treatment with BPAP then transitioned to nocturnal VAPS on discharge. For all patients, dyspnea and pCO2 improved as outpatients although all patients did eventually experience an exacerbation of their lung disease requiring repeat admission. Conclusion Due to the physiologic changes that occur with sleep, patients with severe lung disease may experience worsening CO2 retention while sleeping. There is little data assessing the use of chronic nocturnal non-invasive ventilation (NIV) to treat the hypercapnia of chronic lung diseases other than chronic obstructive pulmonary disease, extra-thoracic restriction, and neuromuscular disease. In this case series, nocturnal VAPS stabilized and/or reduced pCO2 in patients with pulmonary parenchymal disease of various etiologies. Additional studies are needed to assess long term effects of VAPS in these patients, including exacerbations, symptoms, and overall mortality. Support (if any):

scholarly journals Two-hybrid screening of FAM13A protein partners in lung epithelial cells

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Manon Ruffin ◽  
Kristin E. Thompson ◽  
Harriet Corvol ◽  
Loic Guillot
Keyword(s):  
Lung Cancer ◽  
Lung Diseases ◽  
Sequence Similarity ◽  
Lung Epithelial Cells ◽  
Human Lung Cancer ◽  
Chronic Obstructive ◽  
Chronic Lung Diseases ◽  
Protein Partners ◽  
Two Hybrid ◽  
Hybrid Screening

Abstract Objectives Family with sequence similarity 13 member A (FAM13A) genetic variants have been associated with several chronic respiratory diseases including chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF) and lung cancer. The FAM13A protein includes a RhoGTPase activating protein (RhoGAP) domain known to participate in various cellular mechanisms including cell proliferation. While intensive genomic studies have been performed to reveal its involvement in lung diseases, the biological role of FAM13A protein is still not completely elucidated. Results We therefore performed a two-hybrid screening to identify protein partners of FAM13A using a human lung cancer cDNA library. We identified several protein partners with a high confidence score. Researchers in the field of chronic lung diseases may benefit from this two-hybrid screening data which may reveal new research pathways to decipher.

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