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

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

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


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.

TRIAL REGISTRATION:, NCT00467363, Registered April 30, 2007,

Original languageEnglish (US)
Article number60
JournalClinical epigenetics
Issue number1
StatePublished - Apr 30 2020

Bibliographical note

Publisher Copyright:
© 2020 The Author(s).


  • C-reactive protein
  • DNA methylation
  • Developmental programming
  • Inflammation
  • Newborn
  • Pregnancy


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