Cord blood DNA methylation reflects cord blood C-reactive protein levels but not maternal levels: a longitudinal study and meta-analysis

Yeung, Edwina H.; Guan, Weihua; Zeng, Xuehuo; Salas Díaz, Lucas Andrés, 1980-; Mumford, Sunni L.; Prado Bert, Paula de; van Meel, Evelien R.; Malmberg, Anni; Sunyer Deu, Jordi; Duijts, Liesbeth; Felix, Janine Frédérique; Czamara, Darina; Hämäläinen, Esa; Binder, Elisabeth B.; Räikkönen, Katri; Lahti, Jari; London, Stephanie J.; Silver, Robert M.; Schisterman, Enrique F.

Cord blood DNA methylation reflects cord blood C-reactive protein levels but not maternal levels: a longitudinal study and meta-analysis

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dc.contributor.author Yeung, Edwina H.
dc.contributor.author Guan, Weihua
dc.contributor.author Zeng, Xuehuo
dc.contributor.author Salas Díaz, Lucas Andrés, 1980-
dc.contributor.author Mumford, Sunni L.
dc.contributor.author Prado Bert, Paula de
dc.contributor.author van Meel, Evelien R.
dc.contributor.author Malmberg, Anni
dc.contributor.author Sunyer Deu, Jordi
dc.contributor.author Duijts, Liesbeth
dc.contributor.author Felix, Janine Frédérique
dc.contributor.author Czamara, Darina
dc.contributor.author Hämäläinen, Esa
dc.contributor.author Binder, Elisabeth B.
dc.contributor.author Räikkönen, Katri
dc.contributor.author Lahti, Jari
dc.contributor.author London, Stephanie J.
dc.contributor.author Silver, Robert M.
dc.contributor.author Schisterman, Enrique F.
dc.date.accessioned 2020-06-03T06:16:24Z
dc.date.available 2020-06-03T06:16:24Z
dc.date.issued 2020
dc.description.abstract Background: Prenatal inflammation has been proposed as an important mediating factor in several adverse pregnancy outcomes. C-reactive protein (CRP) is an inflammatory cytokine easily measured in blood. It has clinical value due to its reliability as a biomarker for systemic inflammation and can indicate cellular injury and disease severity. Elevated levels of CRP in adulthood are associated with alterations in DNA methylation. However, no studies have prospectively investigated the relationship between maternal CRP levels and newborn DNA methylation measured by microarray in cord blood with reasonable epigenome-wide coverage. Importantly, the timing of inflammation exposure during pregnancy may also result in different effects. Thus, our objective was to evaluate this prospective association of CRP levels measured during multiple periods of pregnancy and in cord blood at delivery which was available in one cohort (i.e., Effects of Aspirin in Gestation and Reproduction trial), and also to conduct a meta-analysis with available data at one point in pregnancy from three other cohorts from the Pregnancy And Childhood Epigenetics consortium (PACE). Secondarily, the impact of maternal randomization to low dose aspirin prior to pregnancy on methylation was assessed. Results: Maternal CRP levels were not associated with newborn DNA methylation regardless of gestational age of measurement (i.e., CRP at approximately 8, 20, and 36 weeks among 358 newborns in EAGeR). There also was no association in the meta-analyses (all p > 0.5) with a larger sample size (n = 1603) from all participating PACE cohorts with available CRP data from first trimester (< 18 weeks gestation). Randomization to aspirin was not associated with DNA methylation. On the other hand, newborn CRP levels were significantly associated with DNA methylation in the EAGeR trial, with 33 CpGs identified (FDR corrected p < 0.05) when both CRP and methylation were measured at the same time point in cord blood. The top 7 CpGs most strongly associated with CRP resided in inflammation and vascular-related genes. Conclusions: Maternal CRP levels measured during each trimester were not associated with cord blood DNA methylation. Rather, DNA methylation was associated with CRP levels measured in cord blood, particularly in gene regions predominately associated with angiogenic and inflammatory pathways.
dc.description.sponsorship This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (National Institutes of Health, Bethesda, MD, USA), and the EAGeR trial was specifically funded under contract numbers HHSN267200603423, HHSN267200603424, HHSN267200603426, and HHSN275201300023I-HHSN2750008. SL was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. Main funding of the epigenetic studies in INMA was grants from Instituto de Salud Carlos III (Red INMA G03/176, CB06/02/0041), Spanish Ministry of Health (FIS-PI04/1436, FIS-PI08/1151 including FEDER funds, FIS-PI11/00610, FIS-FEDER-PI06/0867, FIS-FEDER-PI03-1615, MS13/00054, CP18/00018), Generalitat de Catalunya-CIRIT 1999SGR 00241, Fundació La marató de TV3 (090430), EU Commission (261357-MeDALL: Mechanisms of the Development of ALLergy), and European Research Council (268479-BREATHE: BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn). The general design of the Generation R Study is made possible by financial support from the Erasmus Medical Center, Rotterdam; the Erasmus University Rotterdam; the Netherlands Organization for Health Research and Development; and the Ministry of Health, Welfare and Sport. The EWAS data was funded by a grant from the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO), Netherlands Consortium for Healthy Aging (NCHA; project nr. 050-060-810), by funds from the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, and by a grant from the National Institute of Child and Human Development (R01HD068437). This project received funding from the European Union’s Horizon 2020 research and innovation programme (633595, DynaHEALTH: 733206, LIFECYCLE) and from the European Joint Programming Initiative “A Healthy Diet for a Healthy Life” (JPI HDHL, NutriPROGRAM project, ZonMw the Netherlands no.529051022; and Precise project, ZonMw the Netherlands no. P75416). LD has received funding from the European Joint Programming Initiative. The PREDO study has been funded by the Academy of Finland, EraNet Neuron, EVO (a special state subsidy for health science research), University of Helsinki Research Funds, the Signe and Ane Gyllenberg Foundation, the Emil Aaltonen Foundation, the Finnish Medical Foundation, the Jane and Aatos Erkko Foundation, the Novo Nordisk Foundation, the Päivikki and Sakari Sohlberg Foundation, and the Sigrid Juselius Foundation granted to members of the PREDO study board. Methylation assays were funded by the Academy of Finland.
dc.format.mimetype application/pdf
dc.identifier.citation Yeung EH, Guan W, Zeng X, Salas LA, Mumford SL, de Prado Bert P, van Meel ER, Malmberg A, Sunyer J, Duijts L, Felix JF, Czamara D, Hämäläinen E, Binder EB, Räikkönen K, Lahti J, London SJ, Silver RM, Schisterman EF. Cord blood DNA methylation reflects cord blood C-reactive protein levels but not maternal levels: a longitudinal study and meta-analysis. Clin Epigenetics. 2020; 12(1):60. DOI: 10.1186/s13148-020-00852-2
dc.identifier.doi http://dx.doi.org/10.1186/s13148-020-00852-2
dc.identifier.issn 1868-7075
dc.identifier.uri http://hdl.handle.net/10230/44881
dc.language.iso eng
dc.publisher BioMed Central
dc.relation.ispartof Clin Epigenetics. 2020; 12(1):60
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/261357
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/268479
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/633595
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/733206
dc.rights © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data ma
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.keyword C-reactive protein
dc.subject.keyword DNA methylation
dc.subject.keyword Developmental programming
dc.subject.keyword Inflammation
dc.subject.keyword Newborn
dc.subject.keyword Pregnancy
dc.title Cord blood DNA methylation reflects cord blood C-reactive protein levels but not maternal levels: a longitudinal study and meta-analysis
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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