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Demeo, Dawn

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Demeo, Dawn

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Now showing 1 - 10 of 23
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    Maternal alcohol consumption and offspring DNA methylation: findings from six general population-based birth cohorts
    (Future Medicine Ltd, 2018) Sharp, Gemma C; Arathimos, Ryan; Reese, Sarah E; Page, Christian M; Felix, Janine; Küpers, Leanne K; Rifas-Shiman, Sheryl; Liu, Chunyu; Burrows, Kimberley; Zhao, Shanshan; Magnus, Maria C; Duijts, Liesbeth; Corpeleijn, Eva; Demeo, Dawn; Litonjua, Augusto; Baccarelli, Andrea; Hivert, Marie-France; Oken, Emily; Snieder, Harold; Jaddoe, Vincent; Nystad, Wenche; London, Stephanie J; Relton, Caroline L; Zuccolo, Luisa
    Aim: Alcohol consumption during pregnancy is sometimes associated with adverse outcomes in offspring, potentially mediated by epigenetic modifications. We aimed to investigate genome-wide DNA methylation in cord blood of newborns exposed to alcohol in utero. Materials & methods: We meta-analyzed information from six population-based birth cohorts within the Pregnancy and Childhood Epigenetics consortium. Results: We found no strong evidence of association at either individual CpGs or across larger regions of the genome. Conclusion: Our findings suggest no association between maternal alcohol consumption and offspring cord blood DNA methylation. This is in stark contrast to the multiple strong associations previous studies have found for maternal smoking, which is similarly socially patterned. However, it is possible that a combination of a larger sample size, higher doses, different timings of exposure, exploration of a different tissue and a more global assessment of genomic DNA methylation might show evidence of association.
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    Regulatory network changes between cell lines and their tissues of origin
    (BioMed Central, 2017) Lopes-Ramos, Camila; Paulson, Joseph; Chen, Cho-Yi; Kuijjer, Marieke; Fagny, Maud; Platig, John; Sonawane, Abhijeet; Demeo, Dawn; Quackenbush, John; Glass, Kimberly
    Background: Cell lines are an indispensable tool in biomedical research and often used as surrogates for tissues. Although there are recognized important cellular and transcriptomic differences between cell lines and tissues, a systematic overview of the differences between the regulatory processes of a cell line and those of its tissue of origin has not been conducted. The RNA-Seq data generated by the GTEx project is the first available data resource in which it is possible to perform a large-scale transcriptional and regulatory network analysis comparing cell lines with their tissues of origin. Results: We compared 127 paired Epstein-Barr virus transformed lymphoblastoid cell lines (LCLs) and whole blood samples, and 244 paired primary fibroblast cell lines and skin samples. While gene expression analysis confirms that these cell lines carry the expression signatures of their primary tissues, albeit at reduced levels, network analysis indicates that expression changes are the cumulative result of many previously unreported alterations in transcription factor (TF) regulation. More specifically, cell cycle genes are over-expressed in cell lines compared to primary tissues, and this alteration in expression is a result of less repressive TF targeting. We confirmed these regulatory changes for four TFs, including SMAD5, using independent ChIP-seq data from ENCODE. Conclusions: Our results provide novel insights into the regulatory mechanisms controlling the expression differences between cell lines and tissues. The strong changes in TF regulation that we observe suggest that network changes, in addition to transcriptional levels, should be considered when using cell lines as models for tissues. Electronic supplementary material The online version of this article (10.1186/s12864-017-4111-x) contains supplementary material, which is available to authorized users.
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    Epigenome-wide association study of total serum immunoglobulin E in children: a life course approach
    (BioMed Central, 2018) Peng, Cheng; Cardenas, Andres; Rifas-Shiman, Sheryl; Hivert, Marie-France; Gold, Diane; Platts-Mills, Thomas A.; Lin, Xihong; Oken, Emily; Baccarelli, Andrea A.; Litonjua, Augusto A.; Demeo, Dawn
    Background: IgE-mediated sensitization may be epigenetically programmed in utero, but early childhood environment may further alter complex traits and disease phenotypes through epigenetic plasticity. However, the epigenomic footprint underpinning IgE-mediated type-I hypersensitivity has not been well-understood, especially under a longitudinal early-childhood life-course framework. Methods: We used epigenome-wide DNA methylation (IlluminaHumanMethylation450 BeadChip) in cord blood and mid-childhood peripheral blood to investigate pre- and post-natal methylation marks associated with mid-childhood (age 6.7–10.2) total serum IgE levels in 217 mother-child pairs in Project Viva—a prospective longitudinal pre-birth cohort in eastern Massachusetts, USA. We identified methylation sites associated with IgE using covariate-adjusted robust linear regressions. Results: Nineteen methylation marks in cord blood were associated with IgE in mid-childhood (FDR < 0.05) in genes implicated in cell signaling, growth, and development. Among these, two methylation sites (C7orf50, ZAR1) remained robust after the adjustment for the change in DNA methylation from birth to mid-childhood (FDR < 0.05). An analysis of the change in methylation between cord blood and mid-childhood DNA (Δ-DNAm) identified 395 methylation marks in 272 genes associated with mid-childhood IgE (FDR < 0.05), with multiple sites located within ACOT7 (4 sites), EPX (5 sites), EVL (3 sites), KSR1 (4 sites), ZFPM1 (3 sites), and ZNF862 (3 sites). Several of these methylation loci were previously associated with asthma (ADAM19, EPX, IL4, IL5RA, and PRG2). Conclusion: This study identified fetally programmed and mid-childhood methylation signals associated with mid-childhood IgE. Epigenetic priming during fetal development and early childhood likely plays an important role in IgE-mediated type-I hypersensitivity. Electronic supplementary material The online version of this article (10.1186/s13148-018-0488-x) contains supplementary material, which is available to authorized users.
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    Reduced microRNA-503 expression augments lung fibroblast VEGF production in chronic obstructive pulmonary disease
    (Public Library of Science, 2017) Ikari, Jun; Nelson, Amy J.; Obaid, Jannah; Giron-Martinez, Alvaro; Ikari, Kumiko; Makino, Fumihiko; Iwasawa, Shunichiro; Gunji, Yoko; Farid, Maha; Wang, Xingqi; Basma, Hesham; Demeo, Dawn; Feghali-Bostwick, Carol; Holz, Olaf; Rabe, Klaus; Liu, Xiangde; Rennard, Stephen I.
    Alterations in microRNA (miRNA) expression may contribute to COPD pathogenesis. In COPD, lung fibroblast repair functions are altered in multiple ways, including extracellular mediator release. Our prior study revealed miR-503 expression is decreased in COPD lung fibroblasts, although the exact role played by miR-503 is undetermined. The current study examined a role of miR-503 in cytokine, growth factor and fibronectin production by lung fibroblasts from patients with and without COPD. Primary adult lung fibroblasts were isolated from patients with or without COPD. MiR-503 expression and interleukin (IL)-6, -8, PGE2, HGF, KGF, VEGF and fibronectin release were examined with or without inflammatory cytokines, IL-1β and tumor necrosis factor (TNF)-α. MiR-503 expression was decreased in COPD lung fibroblasts. The expression of miR-503 was positively correlated with %FVC, %FEV1, and %DLco as well as IL-6, -8, PGE2, HGF, KGF, and VEGF in the absence or presence of IL-1ß/TNF-α. In addition, IL-8 and VEGF release from COPD lung fibroblasts were increased compared to those from control. Exogenous miR-503 inhibited VEGF release from primary adult and fetal lung fibroblasts but not IL-8 release. As expected, COPD fibroblasts proliferated more slowly than control fibroblasts. MiR-503 did not affect proliferation of either control or COPD lung fibroblasts. MiR-503 inhibition of VEGF protein production and mRNA was mediated by direct binding to the 3’ untranslated region of VEGF mRNA. Endogenous miR-503 was differently regulated by exogenous stimulants associated with COPD pathogenesis, including IL-1ß/TNF-α, TGF-ß1 and PGE2. Endogenous miR-503 inhibition augmented VEGF release by IL-1ß/TNF-α and TGF-ß1 but not by PGE2, demonstrating selectivity of miR-503 regulation of VEGF. In conclusions, reduced miR-503 augments VEGF release from lung fibroblasts from patients with COPD. Since VEGF contributes to disturbed vasculature in COPD, altered miR-503 production might play a role in modulating fibroblast-mediated vascular homeostasis in COPD.
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    A Simplified Score to Quantify Comorbidity in COPD
    (Public Library of Science, 2014) Putcha, Nirupama; Puhan, Milo A.; Drummond, M. Bradley; Han, MeiLan K.; Regan, Elizabeth A.; Hanania, Nicola A.; Martinez, Carlos H.; Foreman, Marilyn; Bhatt, Surya P.; Make, Barry; Ramsdell, Joe; Demeo, Dawn; Barr, R. Graham; Rennard, Stephen I.; Martinez, Fernando; Silverman, Edwin; Crapo, James; Wise, Robert A.; Hansel, Nadia N.
    Importance Comorbidities are common in COPD, but quantifying their burden is difficult. Currently there is a COPD-specific comorbidity index to predict mortality and another to predict general quality of life. We sought to develop and validate a COPD-specific comorbidity score that reflects comorbidity burden on patient-centered outcomes. Materials and Methods Using the COPDGene study (GOLD II-IV COPD), we developed comorbidity scores to describe patient-centered outcomes employing three techniques: 1) simple count, 2) weighted score, and 3) weighted score based upon statistical selection procedure. We tested associations, area under the Curve (AUC) and calibration statistics to validate scores internally with outcomes of respiratory disease-specific quality of life (St. George's Respiratory Questionnaire, SGRQ), six minute walk distance (6MWD), modified Medical Research Council (mMRC) dyspnea score and exacerbation risk, ultimately choosing one score for external validation in SPIROMICS. Results: Associations between comorbidities and all outcomes were comparable across the three scores. All scores added predictive ability to models including age, gender, race, current smoking status, pack-years smoked and FEV1 (p<0.001 for all comparisons). Area under the curve (AUC) was similar between all three scores across outcomes: SGRQ (range 0·7624–0·7676), MMRC (0·7590–0·7644), 6MWD (0·7531–0·7560) and exacerbation risk (0·6831–0·6919). Because of similar performance, the comorbidity count was used for external validation. In the SPIROMICS cohort, the comorbidity count performed well to predict SGRQ (AUC 0·7891), MMRC (AUC 0·7611), 6MWD (AUC 0·7086), and exacerbation risk (AUC 0·7341). Conclusions: Quantifying comorbidity provides a more thorough understanding of the risk for patient-centered outcomes in COPD. A comorbidity count performs well to quantify comorbidity in a diverse population with COPD.
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    A genome-wide association study identifies risk loci for spirometric measures among smokers of European and African ancestry
    (BioMed Central, 2015) Lutz, Sharon M.; Cho, Michael; Young, Kendra; Hersh, Craig; Castaldi, Peter; McDonald, Merry-Lynn N; Regan, Elizabeth; Mattheisen, Manuel; Demeo, Dawn; Parker, Margaret; Foreman, Marilyn; Make, Barry J.; Jensen, Robert L.; Casaburi, Richard; Lomas, David A.; Bhatt, Surya P.; Bakke, Per; Gulsvik, Amund; Crapo, James D.; Beaty, Terri H.; Laird, Nan; Lange, Christoph; Hokanson, John E.; Silverman, Edwin
    Background: Pulmonary function decline is a major contributor to morbidity and mortality among smokers. Post bronchodilator FEV1 and FEV1/FVC ratio are considered the standard assessment of airflow obstruction. We performed a genome-wide association study (GWAS) in 9919 current and former smokers in the COPDGene study (6659 non-Hispanic Whites [NHW] and 3260 African Americans [AA]) to identify associations with spirometric measures (post-bronchodilator FEV1 and FEV1/FVC). We also conducted meta-analysis of FEV1 and FEV1/FVC GWAS in the COPDGene, ECLIPSE, and GenKOLS cohorts (total n = 13,532). Results: Among NHW in the COPDGene cohort, both measures of pulmonary function were significantly associated with SNPs at the 15q25 locus [containing CHRNA3/5, AGPHD1, IREB2, CHRNB4] (lowest p-value = 2.17 × 10−11), and FEV1/FVC was associated with a genomic region on chromosome 4 [upstream of HHIP] (lowest p-value = 5.94 × 10−10); both regions have been previously associated with COPD. For the meta-analysis, in addition to confirming associations to the regions near CHRNA3/5 and HHIP, genome-wide significant associations were identified for FEV1 on chromosome 1 [TGFB2] (p-value = 8.99 × 10−9), 9 [DBH] (p-value = 9.69 × 10−9) and 19 [CYP2A6/7] (p-value = 3.49 × 10−8) and for FEV1/FVC on chromosome 1 [TGFB2] (p-value = 8.99 × 10−9), 4 [FAM13A] (p-value = 3.88 × 10−12), 11 [MMP3/12] (p-value = 3.29 × 10−10) and 14 [RIN3] (p-value = 5.64 × 10−9). Conclusions: In a large genome-wide association study of lung function in smokers, we found genome-wide significant associations at several previously described loci with lung function or COPD. We additionally identified a novel genome-wide significant locus with FEV1 on chromosome 9 [DBH] in a meta-analysis of three study populations. Electronic supplementary material The online version of this article (doi:10.1186/s12863-015-0299-4) contains supplementary material, which is available to authorized users.
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    A Comparative Study of Tests for Homogeneity of Variances with Application to DNA Methylation Data
    (Public Library of Science, 2015) Li, Xuan; Qiu, Weiliang; Morrow, Jarrett; Demeo, Dawn; Weiss, Scott; Fu, Yuejiao; Wang, Xiaogang
    Variable DNA methylation has been associated with cancers and complex diseases. Researchers have identified many DNA methylation markers that have different mean methylation levels between diseased subjects and normal subjects. Recently, researchers found that DNA methylation markers with different variabilities between subject groups could also have biological meaning. In this article, we aimed to help researchers choose the right test of equal variance in DNA methylation data analysis. We performed systematic simulation studies and a real data analysis to compare the performances of 7 equal-variance tests, including 2 tests recently proposed in the DNA methylation analysis literature. Our results showed that the Brown-Forsythe test and trimmed-mean-based Levene's test had good performance in testing for equality of variance in our simulation studies and real data analyses. Our results also showed that outlier profiles could be biologically very important.
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    Sexually-dimorphic targeting of functionally-related genes in COPD
    (BioMed Central, 2014) Glass, Kimberly; Quackenbush, John; Silverman, Edwin; Celli, Bartolome; Rennard, Stephen I; Yuan, Guo-Cheng; Demeo, Dawn
    Background: There is growing evidence that many diseases develop, progress, and respond to therapy differently in men and women. This variability may manifest as a result of sex-specific structures in gene regulatory networks that influence how those networks operate. However, there are few methods to identify and characterize differences in network structure, slowing progress in understanding mechanisms driving sexual dimorphism. Results: Here we apply an integrative network inference method, PANDA (Passing Attributes between Networks for Data Assimilation), to model sex-specific networks in blood and sputum samples from subjects with Chronic Obstructive Pulmonary Disease (COPD). We used a jack-knifing approach to build an ensemble of likely networks for each sex. By adapting statistical methods to compare these network ensembles, we were able to identify strong differential-targeting patterns associated with functionally-related sets of genes, including those involved in mitochondrial function and energy metabolism. Network analysis also identified several potential sex- and disease-specific transcriptional regulators of these pathways. Conclusions: Network analysis yielded insight into potential mechanisms driving sexual dimorphism in COPD that were not evident from gene expression analysis alone. We believe our ensemble approach to network analysis provides a principled way to capture sex-specific regulatory relationships and could be applied to identify differences in gene regulatory patterns in a wide variety of diseases and contexts. Electronic supplementary material The online version of this article (doi:10.1186/s12918-014-0118-y) contains supplementary material, which is available to authorized users.
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    Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD
    (Public Library of Science, 2016) Sun, Wei; Kechris, Katerina; Jacobson, Sean; Drummond, M. Bradley; Hawkins, Gregory A.; Yang, Jenny; Chen, Ting-huei; Quibrera, Pedro Miguel; Anderson, Wayne; Barr, R. Graham; Basta, Patricia V.; Bleecker, Eugene R.; Beaty, Terri; Casaburi, Richard; Castaldi, Peter; Cho, Michael; Comellas, Alejandro; Crapo, James D.; Criner, Gerard; Demeo, Dawn; Christenson, Stephanie A.; Couper, David J.; Curtis, Jeffrey L.; Doerschuk, Claire M.; Freeman, Christine M.; Gouskova, Natalia A.; Han, MeiLan K.; Hanania, Nicola A.; Hansel, Nadia N.; Hersh, Craig; Hoffman, Eric A.; Kaner, Robert J.; Kanner, Richard E.; Kleerup, Eric C.; Lutz, Sharon; Martinez, Fernando J.; Meyers, Deborah A.; Peters, Stephen P.; Regan, Elizabeth A.; Rennard, Stephen I.; Scholand, Mary Beth; Silverman, Edwin; Woodruff, Prescott G.; O’Neal, Wanda K.; Bowler, Russell P.
    Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p < 8 X 10−10) pQTLs in 38 (43%) of blood proteins tested. Most pQTL SNPs were novel with low overlap to eQTL SNPs. The pQTL SNPs explained >10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group.
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    Variable DNA Methylation Is Associated with Chronic Obstructive Pulmonary Disease and Lung Function
    (American Thoracic Society, 2012) Qiu, Weiliang; Baccarelli, Andrea; Carey, Vincent; Boutaoui, Nadia; Bacherman, Helene; Klanderman, Barbara; Rennard, Stephen; Agusti, Alvar; Anderson, Wayne; Lomas, David A.; Demeo, Dawn
    Rationale: Chronic obstructive pulmonary disease (COPD) is associated with local (lung) and systemic (blood) inflammation and manifestations. DNA methylation is an important regulator of gene transcription, and global and specific gene methylation marks may vary with cigarette smoke exposure. Objectives:Toperformacomprehensive assessmentofmethylationmarks in DNA from subjects well phenotyped for nonneoplastic lung disease. Methods: We conducted array-based methylation screens, using a test-replication approach, in two family-based cohorts (n ¼ 1,085 and 369 subjects). Measurements and Main Results: We observed 349 CpG sites significantly associated with the presence and severity of COPD in both cohorts. Seventy percent of the associated CpG sites were outside of CpG islands, with the majority of CpG sites relatively hypomethylated. Gene ontology analysis based on these 349 CpGs (330 genes) suggested the involvement of a number of genes responsible for immune and inflammatory system pathways, responses to stress and external stimuli, as well as wound healing and coagulation cascades. Interestingly, our observations include significant, replicable associations between SERPINA1 hypomethylation and COPD and lower average lung function phenotypes (combined P values: COPD, 1.5 3 10223; FEV1/FVC, 1.5 3 10235; FEV1, 2.2 3 10240). Conclusions: Genetic and epigenetic pathways may both contribute to COPD. Many of the top associations between COPD and DNA methylation occur in biologically plausible pathways. This largescale analysis suggests that DNA methylation may be a biomarker of COPD and may highlight new pathways of COPD pathogenesis.