scholarly journals DNA methylation is associated with lung function in never smokers

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Maaike de Vries ◽  
◽  
Ivana Nedeljkovic ◽  
Diana A. van der Plaat ◽  
Alexandra Zhernakova ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Lung Function ◽  
Ribosome Biogenesis ◽  
Meta Analysis ◽  
Smoking History ◽  
Rotterdam Study ◽  
Main Risk Factor ◽  
Cpg Sites ◽  
Never Smokers ◽  
Integrative Omics

Abstract Background Active smoking is the main risk factor for COPD. Here, epigenetic mechanisms may play a role, since cigarette smoking is associated with differential DNA methylation in whole blood. So far, it is unclear whether epigenetics also play a role in subjects with COPD who never smoked. Therefore, we aimed to identify differential DNA methylation associated with lung function in never smokers. Methods We determined epigenome-wide DNA methylation levels of 396,243 CpG-sites (Illumina 450 K) in blood of never smokers in four independent cohorts, LifeLines COPD&C (N = 903), LifeLines DEEP (N = 166), Rotterdam Study (RS)-III (N = 150) and RS-BIOS (N = 206). We meta-analyzed the cohort-specific methylation results to identify differentially methylated CpG-sites with FEV1/FVC. Expression Quantitative Trait Methylation (eQTM) analysis was performed in the Biobank-based Integrative Omics Studies (BIOS). Results A total of 36 CpG-sites were associated with FEV1/FVC in never smokers at p-value< 0.0001, but the meta-analysis did not reveal any epigenome-wide significant CpG-sites. Of interest, 35 of these 36 CpG-sites have not been associated with lung function before in studies including subjects irrespective of smoking history. Among the top hits were cg10012512, cg02885771, annotated to the gene LTV1 Ribosome Biogenesis factor (LTV1), and cg25105536, annotated to Kelch Like Family Member 32 (KLHL32). Moreover, a total of 11 eQTMS were identified. Conclusions With the identification of 35 CpG-sites that are unique for never smokers, our study shows that DNA methylation is also associated with FEV1/FVC in subjects that never smoked and therefore not merely related to smoking.

scholarly journals Novel DNA methylation signatures of tobacco smoking with trans-ethnic effects

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
C. Christiansen ◽  
J. E. Castillo-Fernandez ◽  
A. Domingo-Relloso ◽  
W. Zhao ◽  
J. S. El-Sayed Moustafa ◽  
...  
Keyword(s):  
Dna Methylation ◽  
African American ◽  
American Indian ◽  
Birth Cohort ◽  
Disease Risk ◽  
Meta Analysis ◽  
Cpg Islands ◽  
Cpg Sites ◽  
Never Smokers ◽  
Epic Array

Abstract Background Smoking remains one of the leading preventable causes of death. Smoking leaves a strong signature on the blood methylome as shown in multiple studies using the Infinium HumanMethylation450 BeadChip. Here, we explore novel blood methylation smoking signals on the Illumina MethylationEPIC BeadChip (EPIC) array, which also targets novel CpG-sites in enhancers. Method A smoking-methylation meta-analysis was carried out using EPIC DNA methylation profiles in 1407 blood samples from four UK population-based cohorts, including the MRC National Survey for Health and Development (NSHD) or 1946 British birth cohort, the National Child Development Study (NCDS) or 1958 birth cohort, the 1970 British Cohort Study (BCS70), and the TwinsUK cohort (TwinsUK). The overall discovery sample included 269 current, 497 former, and 643 never smokers. Replication was pursued in 3425 trans-ethnic samples, including 2325 American Indian individuals participating in the Strong Heart Study (SHS) in 1989–1991 and 1100 African-American participants in the Genetic Epidemiology Network of Arteriopathy Study (GENOA). Results Altogether 952 CpG-sites in 500 genes were differentially methylated between smokers and never smokers after Bonferroni correction. There were 526 novel smoking-associated CpG-sites only profiled by the EPIC array, of which 486 (92%) replicated in a meta-analysis of the American Indian and African-American samples. Novel CpG sites mapped both to genes containing previously identified smoking-methylation signals and to 80 novel genes not previously linked to smoking, with the strongest novel signal in SLAMF7. Comparison of former versus never smokers identified that 37 of these sites were persistently differentially methylated after cessation, where 16 represented novel signals only profiled by the EPIC array. We observed a depletion of smoking-associated signals in CpG islands and an enrichment in enhancer regions, consistent with previous results. Conclusion This study identified novel smoking-associated signals as possible biomarkers of exposure to smoking and may help improve our understanding of smoking-related disease risk.

scholarly journals P13.15 DNA methylation abnormalities in non-promoter regulatory regions are associated with invasive behavior in pituitary tumors

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii65-iii66
Author(s):  
M Q S Mosella ◽  
T S Sabedot ◽  
T M Malta ◽  
J Rock ◽  
M Felicella ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Target Genes ◽  
Meta Analysis ◽  
Differentially Expressed Gene ◽  
Cell Movement ◽  
Pituitary Tumors ◽  
P Value ◽  
Regulatory Regions ◽  
Cpg Sites ◽  
Invasive Behavior

Abstract BACKGROUND Despite histologically benign, pituitary tumors (PT) may invade important adjacent neurovascular structures which can incur in significant comorbidities preventing a complete surgical resection and contributing to resistance to medical treatment. DNA methylation clearly stratified PT based on their functional status i.e. nonfunctioning PTs (NFPTs) from functioning PT (FPTs). However associations of methylation aberrations with invasive behavior is less clear. MATERIAL AND METHODS In order to evaluate whether DNA methylation alterations in regulatory regions other than promoter and coding regions are associated with invasive behavior we performed a meta-analysis of the genome-wide methylome of three public available PT cohorts plus our own (Illumina HumanMethylation platforms- 450K/EPIC). Pituitary specimens comprised of 43 invasive pituitary tumors (InvPT) and 37 noninvasive (NInvPT); 12 FPT and 68 NFPTs, in addition to 20 non-tumor pituitaries. RNA-seq data were available for one cohort (n=23, 12 InvPT,11NInvPT) and integrated with DNA methylation. Invasiveness criteria was based on Knosp grade >= 2 and/or sphenoid or dural invasion. RESULTS Wilcoxon Rank-sum test; Δβ=0.15; p-value <0.001 identified 58 differentially methylated CpG sites in InvPT that were mainly hypomethylated (95%) in relation to NInvPT. NInvPT methylation profile was similar to non-tumor specimens, despite its heterogeneity. Thirty-four percent (n=20) of the differentially methylated CpG sites were located within predicted enhancer regions distributed in intronic (40%), intergenic (40%) and promoter (20%) regions. Predicted enhancer-target genes were enriched for actin filament cell movement, response to starvation, growth factor stimulus and protein autophosporilation pathways. Among them, ZNF625 and INO80E were found mostly negative correlated among methylation and expression data (-0.50 and -0.48, respectively), besides DOC2A found to be one potentially differentially expressed gene under enhancer control (log2FC > 0.2, pvalue <0.05). CONCLUSION Our results suggest that methylation alterations in predicted regulatory regions, such as enhancers, annotated in non-promoter regions (introns and intergenic) may contribute to the invasive behavior of PT.

Effect of smoking on the efficacy of immune checkpoint inhibitors in advanced cancers: A systematic review and meta-analysis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14109-e14109
Author(s):  
Chia Ching Lee ◽  
Ivan Weng Keong Tham ◽  
Yu Yang Soon ◽  
Jeremy Chee Seong Tey
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Smoking Status ◽  
Meta Analysis ◽  
Random Effect ◽  
Standard Of Care ◽  
Smoking History ◽  
P Value ◽  
Never Smokers

e14109 Background: The association between smoking history and benefit from treatment with immune checkpoint inhibitors (ICIs) was unclear. We performed a meta-analysis to assess the efficacy of ICIs in advanced cancers according to smoking status (never-smokers vs ever-smokers). Methods: We searched MEDLINE and EMBASE for randomized controlled trials (RCTs) comparing immunotherapy with standard-of-care in the treatment of advanced cancers which reported overall survival (OS) as the outcome, stratified by smoking status. We calculated pooled hazard ratios (HRs) and 95% confidence interval (CIs) for OS using random-effect models and assessed the differences in OS between the two estimates (never smoker (vs) ever smoker). using a test of heterogeneity. We also performed prespecified subgroup analyses based on disease site, line of therapy, proportion of never-smokers in the trials and trial conclusion to assess the potential association of oncologic and methodologic factors in effect modification of smoking status with the efficacy of ICIs. Results: We identified ten RCTs on non-small cell lung cancer, head and neck, and urothelial cancers, including 4,245 ever-smokers and 972 never-smokers. The difference in the effects of ICIs on OS between ever-smokers (HR, 0.74; 95% CI, 0.66-0.84) and never-smokers (HR, 0.79; 95% CI, 0.61-1.02) was not statistically significant (interaction P-value = 0.69). There were no significant differences in the effects of ICIs on OS between ever-smokers and never smokers in the pre-specified subgroups. Conclusions: There was no significant association between smoking status and improved survival outcome with ICIs in the treatment of advanced cancers. Smoking status should not be used as a biomarker for guiding treatment with immunotherapy.

Integration of public DNA methylation and expression networks via eQTMs improves prediction of functional gene-gene associations

2021 ◽  
Author(s):  
Shuang Li ◽  
Cancan Qi ◽  
Patrick Deelen ◽  
Floranne Boulogne ◽  
Niek de Klein ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Gene Networks ◽  
Prediction Models ◽  
Meta Analysis ◽  
Rna Seq ◽  
Integrated Network ◽  
Functional Relationships ◽  
Cpg Sites ◽  
Molecular Phenotypes ◽  
Public Datasets

Gene co-expression networks can be used to infer functional relationships between genes, but they do not work well for all genes. We investigated whether DNA methylation can provide complementary information for such genes. We first carried out an eQTM meta-analysis of 3,574 gene expression and methylation samples from blood, brain and nasal epithelial brushed cells to identify links between methylated CpG sites and genes. This revealed 6,067 significant eQTM genes, and we observed that histone modification information is predictive of both eQTM direction and presence, enabling us to link many CpG sites to genes. We then generated a co-methylation network - MethylationNetwork - using 27,720 publicly available methylation profiles and integrated it with a public RNA-seq co-expression dataset of 31,499 samples. Here, we observed that MethylationNetwork can identify experimentally validated interacting pairs of genes that could not be identified in the RNA-seq datasets. We then developed a novel integration pipeline based on CCA and used the integrated methylation and gene networks to predict gene pairs reported in the STRING database. The integrated network showed significantly improved prediction performance compared to using a DNA co-methylation or a gene co-expression network alone. This is the first study to integrate data from two -omics layers from unmatched public samples across different tissues and diseases, and our results highlight the issues and potential of integrating public datasets from multiple molecular phenotypes. The eQTMs we identified can be used as an annotation resource for epigenome-wide association, and we believe that our integration pipeline can be used as a framework for future -omics integration analyses of public datasets. We provide supporting materials and results, including the harmonized DNA methylation data from multiple tissues and diseases in https://data.harmjanwestra.nl/comethylation/, the discovered and predicted eQTMs, the corresponding CCA components and the trained prediction models in a Zenodo repository (https://zenodo.org/record/4666994). We provide notebooks to facilitate use of the proposed pipeline in a GitHub repository (https://github.com/molgenis/methylationnetwork).

scholarly journals Meta‐analysis of genome‐wide DNA methylation and integrative omics of age in human skeletal muscle

2021 ◽  
Author(s):  
Sarah Voisin ◽  
Macsue Jacques ◽  
Shanie Landen ◽  
Nicholas R. Harvey ◽  
Larisa M. Haupt ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Dna Methylation ◽  
Human Skeletal Muscle ◽  
Meta Analysis ◽  
Genome Wide ◽  
Integrative Omics

scholarly journals Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies novel methylation loci

2019 ◽  
Author(s):  
Alicia K Smith ◽  
Andrew Ratanatharathorn ◽  
Adam X Maihofer ◽  
Robert K Naviaux ◽  
Allison E Aiello ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stress Disorder ◽  
Smoking Status ◽  
Meta Analysis ◽  
Biological Processes ◽  
Metabolomics Data ◽  
Cpg Sites ◽  
Aryl Hydrocarbon ◽  
Analysis Strategy ◽  
Insight Into

AbstractDifferences in susceptibility to posttraumatic stress disorder (PTSD) may be related to epigenetic differences between PTSD cases and trauma-exposed controls. Such epigenetic differences may provide insight into the biological processes underlying the disorder. Here we describe the results of the largest DNA methylation meta-analysis of PTSD to date with data from the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup. Ten cohorts, military and civilian, contributed blood-derived DNA methylation data (HumanMethylation450 BeadChip) from 1,896 PTSD cases (42%) and trauma-exposed controls (58%). Utilizing a common QC and analysis strategy, we identified ten CpG sites associated with PTSD (9.61E-07<p<4.72E-11) after adjustment for multiple comparisons (FDR<.05). Several CpGs were located in genes previously implicated in PTSD and other psychiatric disorders. The top four CpG sites fell within the aryl-hydrocarbon receptor repressor (AHRR) locus and were associated with lower DNA methylation in PTSD cases relative to controls. Interestingly, this association appeared to uncorrelated with smoking status and was most pronounced in non-smokers with PTSD. Additional evaluation of metabolomics data supported our findings and revealed that AHRR methylation associated with kynurenine levels, which were lower among subjects with PTSD relative to controls. Overall, this study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.

scholarly journals Epigenome-wide association study of lung function in Latino children and youth with asthma

2022 ◽  
Vol 14 (1) ◽  
Author(s):  
Esther Herrera-Luis ◽  
Annie Li ◽  
Angel C. Y. Mak ◽  
Javier Perez-Garcia ◽  
Jennifer R. Elhawary ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Lung Function ◽  
Association Study ◽  
Whole Blood ◽  
Mexican Americans ◽  
Mexican American ◽  
Puerto Ricans ◽  
Cpg Sites ◽  
Significance Threshold ◽  
American Children

Abstract Introduction DNA methylation studies have associated methylation levels at different CpG sites or genomic regions with lung function. Moreover, genetic ancestry has been associated with lung function in Latinos. However, no epigenome-wide association study (EWAS) of lung function has been performed in this population. Here, we aimed to identify DNA methylation patterns associated with lung function in pediatric asthma among Latinos. Results We conducted an EWAS in whole blood from 250 Puerto Rican and 148 Mexican American children and young adults with asthma. A total of five CpGs exceeded the genome-wide significance threshold of p = 1.17 × 10−7 in the combined analyses from Puerto Ricans and Mexican Americans: cg06035600 (MAP3K6, p = 6.13 × 10−8) showed significant association with pre-bronchodilator Tiffeneau–Pinelli index, the probes cg00914963 (TBC1D16, p = 1.04 × 10−7), cg16405908 (MRGPRE, p = 2.05 × 10−8), and cg07428101 (MUC2, p = 5.02 × 10−9) were associated with post-bronchodilator forced vital capacity (FVC), and cg20515679 (KCNJ6) with post-bronchodilator Tiffeneau–Pinelli index (p = 1.13 × 10−8). However, these markers did not show significant associations in publicly available data from Europeans (p > 0.05). A methylation quantitative trait loci analysis revealed that methylation levels at these CpG sites were regulated by genetic variation in Latinos and the Biobank-based Integrative Omics Studies (BIOS) consortium. Additionally, two differentially methylated regions in REXOC and AURKC were associated with pre-bronchodilator Tiffeneau–Pinelli index (adjusted p < 0.05) in Puerto Ricans and Mexican Americans. Moreover, we replicated some of the previous differentially methylated signals associated with lung function in non-Latino populations. Conclusions We replicated previous associations of epigenetic markers with lung function in whole blood and identified novel population-specific associations shared among Latino subgroups.

scholarly journals Peripheral blood DNA methylation and autism spectrum disorder

2018 ◽  
Author(s):  
Shan V. Andrews ◽  
Brooke Sheppard ◽  
Gayle C. Windham ◽  
Laura A. Schieve ◽  
Diana E. Schendel ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Dna Methylation ◽  
Sample Size ◽  
Meta Analysis ◽  
Autism Spectrum ◽  
Case Control ◽  
Small Sample ◽  
Spectrum Disorder ◽  
Blood Samples ◽  
Cpg Sites

AbstractBackgroundSeveral reports have suggested a role for epigenetic mechanisms in ASD etiology. Epigenome-wide association studies (EWAS) in autism spectrum disorder (ASD) may shed light on particular biological mechanisms. However, studies of ASD cases versus controls have been limited by post-mortem timing and severely small sample sizes. Reports from in-life sampling of blood or saliva have also been very limited in sample size, and/or genomic coverage. We present the largest case-control EWAS for ASD to date, combining data from population-based case-control and case-sibling pair studies.MethodsDNA from 968 blood samples from children in the Study to Explore Early Development (SEED 1) was used to generate epigenome-wide array DNA methylation (DNAm) data at 485,512 CpG sites for 453 cases and 515 controls, using the Illumina 450K Beadchip. The Simons Simplex Collection (SSC) provided 450K array DNAm data on an additional 343 cases and their unaffected siblings. We performed EWAS meta-analysis across results from the two data sets, with adjustment for sex and surrogate variables that reflect major sources of biological variation and technical confounding such as cell type, batch, and ancestry. We compared top EWAS results to those from a previous brain-based analysis. We also tested for enrichment of ASD EWAS CpGs for being targets of meQTL associations using available SNP genotype data in the SEED sample.FindingsIn this meta-analysis of blood-based DNA from 796 cases and 858 controls, no single CpG met a Bonferroni discovery threshold of p < 1.12×10−7. Seven CpGs showed differences at p < 1×10−5 and 48 at 1×10−4. Of the top 7, 5 showed brain-based ASD associations as well, often with larger effect sizes, and the top 48 overall showed modest concordance (r = 0.31) in direction of effect with cerebellum samples. Finally, we observed suggestive evidence for enrichment of CpG sites controlled by SNPs (meQTL targets) among the EWAS CpGs hits, which was consistent across EWAS and meQTL discovery p-value thresholds.ConclusionsWe report the largest case-control EWAS study of ASD to date. No single CpG site showed a large enough DNAm difference between cases and controls to achieve epigenome-wide significance in this sample size. However, our results suggest the potential to observe disease associations from blood-based samples. Among the 7 sites achieving suggestive statistical significance, we observed consistent, and stronger, effects at the same sites among brain samples. Discovery-oriented EWAS for ASD using blood samples will likely need even larger samples and unified genetic data to further understand DNAm differences in ASD.

scholarly journals Association of Assisted Reproductive Technologies with offspring cord blood DNA methylation across cohorts

2020 ◽  
Author(s):  
Doretta Caramaschi ◽  
James Jungius ◽  
Christian M. Page ◽  
Boris Novakovic ◽  
Richard Saffery ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cord Blood ◽  
Study Design ◽  
Assisted Reproductive Technologies ◽  
Biological Effects ◽  
Meta Analysis ◽  
Reproductive Technologies ◽  
P Value ◽  
Cpg Sites

AbstractStudy questionIs DNA methylation at birth associated with having been conceived by assisted reproductive technologies (ART)?Summary answerThis study shows does not provide strong evidence of an association of conception by ART with variation in infant blood cell DNA methylation.What is known alreadyAssisted reproductive technologies (ART) are procedures used to help infertile/subfertile couples conceive. Due to its importance in gene regulation during early development programming, DNA methylation and its perturbations associated with ART could reveal new insights into the biological effects of ART and potential adverse offspring outcomes.Study designWe investigated the association of DNA methylation and ART using a case-control study design (N=205 ART cases and N=2439 non-ART controls in discovery cohorts; N=149 ART cases and N=58 non-ART controls in replication cohort).Participants/materials, settings, methodWe assessed the association between ART and DNA methylation at birth in cord blood (205 ART conceptions and 2439 naturally conceived controls) at >450000 CpG sites across the genome in two sub-samples of the UK Avon Longitudinal Study of Parents and Children (ALSPAC) and two sub-samples of the Norwegian Mother, Father and Child Cohort Study (MoBa) by meta-analysis. We explored replication of findings in the Australian Clinical review of the Health of adults conceived following Assisted Reproductive Technologies (CHART) study (N=149 ART conceptions and N=58 controls).Main results and the role of chanceThe ALSPAC and MoBa meta-analysis revealed evidence of association between conception by ART and DNA methylation (false-discovery-rate-corrected p-value < 0.05) at 5 CpG sites which are annotated to 2 genes. Methylation at 3 of these sites has been previously linked to cancer, aging, HIV infection and neurological diseases. None of these associations replicated in the CHART cohort. There was evidence of a functional role of ART-induced hypermethylation at CpG sites located within regulatory regions as shown by putative transcription factor binding and chromatin remodelling.Limitations, reasons for cautionsWhile insufficient power is likely, heterogeneity in types of ART and between populations may also contribute. Larger studies might identify replicable variation in DNA methylation at birth due to ART.Wider implications of the findingsART-conceived newborns present with divergent DNA methylation in cord blood white cells. If these associations are true and causal, they might have long-term consequences for offspring health.

Sign in / Sign up

Export Citation Format

Share Document