Longitudinal effects of smoking cessation on DNA methylation in bronchial biopsies of COPD and asymptomatic smokers

Author(s):  
Alen Faiz ◽  
Senani N.H. Rathnayake ◽  
Corneelis Vermeulen ◽  
Wim Timens ◽  
Wierd Kooistra ◽  
...  
2019 ◽  
Vol 24 (6) ◽  
pp. 493-500 ◽  
Author(s):  
Carol Mitchell ◽  
Megan E Piper ◽  
Stevens S Smith ◽  
Claudia E Korcarz ◽  
Michael C Fiore ◽  
...  

Carotid artery grayscale ultrasound echogenicity and texture features predict cardiovascular disease events. We evaluated the longitudinal effects of smoking cessation on four grayscale ultrasound measures. This was a secondary analysis of data from 188 age, sex, and body mass index (BMI)-matched smokers (94 eventual abstainers [EA], 94 continued smokers [CS]) from a smoking cessation trial that had carotid ultrasound examinations at baseline and after 3 years. General linear models that included time, smoking group (EA or CS), and a time*smoking interaction term were used to examine the impact of smoking abstinence on carotid artery grayscale marker values at year 3. Participants were mean (SD) 50.3 (11.4) years old (57% female, 86% white). The baseline grayscale median value (GSM) was inversely correlated with age, BMI, insulin resistance, and smoking pack-years ( r = −0.20 to –0.30, p < 0.007 for all). There was a significant time*smoking status interaction for predicting GSM at year 3: GSM decreased significantly in the EA group compared to the CS group (–3.63 [13.00] vs CS 0.39 [12.06] units; p = 0.029). BMI increased more in the EA than the CS group (2.42 [3.00] vs CS 0.35 [2.57] kg/m2; p < 0.001). After adjusting for changes in BMI, the time*smoking status interaction no longer was significant ( p = 0.138). From baseline to year 3, contrast increased similarly in both groups. Entropy and angular second moment did not change significantly in either group. Changes in carotid ultrasound echogenicity and grayscale texture features during a smoking cessation attempt are modest and mostly related to weight gain. Clinicaltrials.gov Identifier: NCT01553084


2020 ◽  
Vol 315 ◽  
pp. 62-67
Author(s):  
James H. Stein ◽  
Stevens S. Smith ◽  
Kristin M. Hansen ◽  
Claudia E. Korcarz ◽  
Megan E. Piper ◽  
...  

2016 ◽  
Vol 13 (1) ◽  
pp. 1-5 ◽  
Author(s):  
Paul D. Loprinzi ◽  
Jerome F. Walker

Objective:To our knowledge, no longitudinal epidemiological study among daily smokers has examined the effects of physical activity change/trajectory on smoking cessation. The purpose of this study was to examine the longitudinal effects of changes in physical activity on smoking cessation among a national sample of young (16–24 y) daily smokers.Methods:Data from the 2003–2005 National Youth Smoking Cessation Survey were used (N = 1178). Using hierarchical agglomerative cluster analysis, 5 distinct self-reported physical activity trajectories over 3 time periods (baseline, 12-month, and 24-month follow-up) were observed, including stable low physical activity, decreasing physical activity, curvilinear physical activity, stable high physical activity, and increasing physical activity. Nicotine dependence (Heaviness of Smoking Index) and demographic parameters were assessed via survey.Results:With stable low physical activity (16.2% quit smoking) serving as the referent group, those in the stable high physical activity (24.8% quit smoking) group had 1.8 greater odds of not smoking at the 24-month follow-up period (odds ratio = 1.81; 95% confidence interval, 1.12–2.91) after adjusting for nicotine dependence, age, gender, race-ethnicity, and education.Conclusions:Maintenance of regular physical activity among young daily smokers may help to facilitate smoking cessation.


2019 ◽  
Vol 55 (2) ◽  
pp. 1901280 ◽  
Author(s):  
Cornelis J. Vermeulen ◽  
Cheng-Jian Xu ◽  
Judith M. Vonk ◽  
Nick H.T. ten Hacken ◽  
Wim Timens ◽  
...  

Approximately 40% of asthmatics experience remission of asthma symptoms. A better understanding of biological pathways leading to asthma remission may provide insight into new therapeutic targets for asthma. As an important mechanism of gene regulation, investigation of DNA methylation provides a promising approach. Our objective was to identify differences in epigenome wide DNA methylation levels in bronchial biopsies between subjects with asthma remission and subjects with persistent asthma or healthy controls.We analysed differential DNA methylation in bronchial biopsies from 26 subjects with persistent asthma, 39 remission subjects and 70 healthy controls, using the limma package. The comb-p tool was used to identify differentially methylated regions. DNA methylation of CpG-sites was associated to expression of nearby genes from the same biopsies to understand function.Four CpG-sites and 42 regions were differentially methylated between persistent asthma and remission. DNA methylation at two sites was correlated incis with gene expression at ACKR2 and DGKQ. Between remission subjects and healthy controls 1163 CpG-sites and 328 regions were differentially methylated. DNA methylation was associated with expression of a set of genes expressed in ciliated epithelium.CpGs differentially methylated between remission and persistent asthma identify genetic loci associated with resolution of inflammation and airway responsiveness. Despite the absence of symptoms, remission subjects have a DNA methylation profile that is distinct from that of healthy controls, partly due to changes in cellular composition, with a higher gene expression signal related to ciliated epithelium in remission versus healthy controls.


Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2554-2554
Author(s):  
Mary Figueroa ◽  
Mansour Alfayez ◽  
Yue Lu ◽  
Marcos Estecio ◽  
Seyed Javad Moghaddam ◽  
...  

Subsets of acute myelogenous leukemia (AML) are characterized by molecular alterations with prognostic significance, however, little is known about how modifiable behaviors, such as cigarette smoking, intersect with genetic factors. Mutations rendering the Fms-like tyrosine kinase 3 (FLT3) constitutively active, such as internal tandem duplication (ITD), are associated with refractory disease and therapy resistance. Inhibition of the FLT3 kinase shows some benefit in this population, as highlighted by the FDA approvals of midostaurin and gilteritinib, but overall outcomes remain poor. Cigarette smoke exposure (CSE) also marks a population of patients with poor prognosis. Current and former smokers who develop AML are known to have worse survival as compared to never smokers (Alfayez M., et al. ASCO 2019), but the impact of FLT3 mutation and subsequent associated treatment response has not been studied. Also, the underlying mechanism of how history of cigarette smoking influences leukemia biology and response to therapy is poorly understood. In order to model a history of smoking in AML patients, NOD-SCID mice (n=25) were exposed to CSE using a smoking robot for 2 hours, 5 days/week, for 2 weeks. Mice were then inoculated via tail-vein injection with luciferase tagged human FLT3-ITD cells and leukemia burden was monitored through noninvasive imaging. CSE continued through the duration of the experiment, post engraftment. Control "non-smoking" mice (n=15) were only injected with leukemia cells. Within one week post leukemic introduction, a significant increase in leukemic burden as measured by bioluminescence was apparent in mice exposed to CSE versus control mice (P-value<0.0001). To model the impact of smoking cessation upon diagnosis of AML in patients, experiments were modified to halt CSE once leukemic engraftment was detectable by non-invasive imaging. Smoking cessation versus continuous smoke exposure yielded reduced relative leukemic burden. Mice with continuous smoke exposure had higher rates of leukemia compared to mice who ceased smoking (n=10) one week prior (P-value =0.0064). These rapid changes in leukemic burden suggest that CSE may prime the microenvironment to promote leukemia progression or directly affect leukemia cells. To address the latter possibility, human AML cells were exposed to cigarette smoke condensate (CSC), which contains the chemicals present in cigarettes, for two weeks before introducing the cells into mice. A significant increase in leukemic burden was observed in mice injected cells exposed to CSC compared to mice injected with unexposed leukemia cells (P-value <0.001), highlighting a direct role for the chemicals in cigarettes on in vivo leukemia proliferative factors. Smokers are known to carry altered global DNA methylation signatures that persist decades after quitting. To measure DNA methylation changes in the in vivo models described above, we examined spleens of non-smoking and smoke exposed mice by reduced representative bisulfite sequencing (RRBS). Sequences were mapped to either the human or mouse genome, (enabling identification of leukemia specific versus microenvironment specific alterations) and were compared in the smoking and non-smoking mice. Over 200 genes exhibited significant DNA methylation alterations in their promoter regions. Genes involved in RNA polymerase activity and chromatin remodeling were highly represented amongst those with altered DNA methylation. The clinical significance of our observations was confirmed in a cohort of 58 treatment naïve FLT3-ITD AML patients at MD Anderson receiving intensive induction therapy: 41 never smokers and 17 ever smokers. Smokers had significantly reduced survival as compared to the never smokers (median overall survival of 18 vs 23 months, P-value 0.0092). Collectively our findings indicate that short-term CSE is sufficient to alter DNA methylation patterns and accelerate the early progression of FLT3-ITD AML in vivo. Smoking cessation upon diagnosis may slow leukemic growth relative to smoking throughout AML therapy prompting the consideration of behavioral interventions for smokers with AML. Improved understanding of the mechanism of leukemic progression and drug resistance from CSE is expected to lead to improved treatment paradigms designed for patients with a history of cigarette smoking. Disclosures Konopleva: Genentech: Honoraria, Research Funding; Kisoji: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Ascentage: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Astra Zeneca: Research Funding; Agios: Research Funding. Jabbour:Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding. DiNardo:agios: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; jazz: Honoraria; medimmune: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; daiichi sankyo: Honoraria; syros: Honoraria; celgene: Consultancy, Honoraria.


2020 ◽  
Vol 117 ◽  
pp. 104656
Author(s):  
Erika J. Wolf ◽  
Mark W. Logue ◽  
Xiang Zhao ◽  
Nikolaos P. Daskalakis ◽  
Filomene G. Morrison ◽  
...  

2009 ◽  
Vol 2009 ◽  
pp. 1-8 ◽  
Author(s):  
Izolde Bouloukaki ◽  
Maria Tsoumakidou ◽  
Constantine I. Vardavas ◽  
Ioanna Mitrouska ◽  
Eleni Koutala ◽  
...  

Little is known about the longitudinal effects of smoking cessation on sputum inflammatory cells. We aimed to investigate the changes in sputum inflammatory cells and T-lymphocyte subpopulations after 6 and 12 months smoking cessation. Induced sputum was obtained from 68 healthy smokers before and after 6 months (n=21) and 1 year (n=14) smoking cessation and from ten healthy never-smokers. Inflammatory cells were identified by morphology and T-lymphocyte subpopulations by flow cytometry. Sputum macrophages were decreased after 12 months of smoking cessation in comparison to baseline, while neutrophils increased. Moreover,CD8+T-cells were decreased in smokers before smoking cessation compared to never-smokers and increased in smokers after 6 months of smoking cessation in comparison to baseline; result that was maintained after 1 year of smoking cessation. These novel findings indicate that smoking cessation can equilibrate certain inflammatory cells of smokers with those of nonsmokers, within 6 months of smoking cessation.


Biomolecules ◽  
2018 ◽  
Vol 8 (3) ◽  
pp. 74 ◽  
Author(s):  
Tina Haase ◽  
Christian Müller ◽  
Julia Krause ◽  
Caroline Röthemeier ◽  
Justus Stenzig ◽  
...  

Smoking is a major risk factor for cardiovascular diseases and has been implicated in the regulation of the G protein-coupled receptor 15 (GPR15) by affecting CpG methylation. The G protein-coupled receptor 15 is involved in angiogenesis and inflammation. An effect on GPR15 gene regulation has been shown for the CpG site CpG3.98251294. We aimed to analyze the effect of smoking on GPR15 expression and methylation sites spanning the GPR15 locus. DNA methylation of nine GPR15 CpG sites was measured in leukocytes from 1291 population-based individuals using the EpiTYPER. Monocytic GPR15 expression was measured by qPCR at baseline and five-years follow up. GPR15 gene expression was upregulated in smokers (beta (ß) = −2.699, p-value (p) = 1.02 × 10−77) and strongly correlated with smoking exposure (ß = −0.063, p = 2.95 × 10−34). Smoking cessation within five years reduced GPR15 expression about 19% (p = 9.65 × 10−5) with decreasing GPR15 expression over time (ß = 0.031, p = 3.81 × 10−6). Additionally, three novel CpG sites within GPR15 affected by smoking were identified. For CpG3.98251047, DNA methylation increased steadily after smoking cessation (ß = 0.123, p = 1.67 × 10−3) and strongly correlated with changes in GPR15 expression (ß = 0.036, p = 4.86 × 10−5). Three novel GPR15 CpG sites were identified in relation to smoking and GPR15 expression. Our results provide novel insights in the regulation of GPR15, which possibly linked smoking to inflammation and disease progression.


2018 ◽  
Author(s):  
Daniel L McCartney ◽  
Anna J Stevenson ◽  
Robert F Hillary ◽  
Rosie M Walker ◽  
Mairead L Bermingham ◽  
...  

AbstractBackgroundMultiple studies have made robust associations between differential DNA methylation and exposure to cigarette smoke. But whether a DNA methylation phenotype is established immediately upon exposure, or only after prolonged exposure is less well-established. Here, we assess DNA methylation patterns in current smokers in response to dose and duration of exposure, along with the effects of smoking cessation on DNA methylation in former smokers.MethodsDimensionality reduction was applied to DNA methylation data at 90 previously identified smoking-associated CpG sites for over 4,900 individuals in the Generation Scotland cohort. K-means clustering was performed to identify clusters associated with current and never smoker status based on these methylation patterns. Cluster assignments were assessed with respect to duration of exposure in current smokers (years as a smoker), time since smoking cessation in former smokers (years), and dose (cigarettes per day).ResultsTwo clusters were specified, corresponding to never smokers (97.5% of whom were assigned to Cluster 1) and current smokers (81.1% of whom were assigned to Cluster 2). The exposure time point from which >50% of current smokers were assigned to thesmoker-enrichedcluster varied between 5-9 years in heavier smokers and between 15-19 years in lighter smokers. Low-dose former smokers were more likely to be assigned to thenever smoker-enrichedcluster from the first year following cessation. In contrast, a period of at least two years was required before the majority of former high-dose smokers were assigned to the never smoker-enriched cluster.ConclusionsOur findings suggest that smoking-associated DNA methylation changes are a result of prolonged exposure to cigarette smoke, and can be reversed following cessation. The length of time in which these signatures are established and recovered is dose dependent. Should DNA methylation-based signatures of smoking status be predictive of smoking-related health outcomes, our findings may provide an additional criterion on which to stratify risk.


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