Abstract
BackgroundPrenatal 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.ResultsMaternal 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.ConclusionsMaternal 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 registrationClinicaltrials.gov, NCT00467363, Registered April 30, 2007, http://www.clinicaltrials.gov/ct2/show/NCT00467363
Highlights
Prenatal inflammation has been proposed as an important mediating factor in several adverse pregnancy outcomes
Maternal C-reactive protein (CRP) levels measured during each trimester were not associated with cord blood Deoxyribonucleic acid (DNA) methylation
DNA methylation was associated with CRP levels measured in cord blood, in gene regions predominately associated with angiogenic and inflammatory pathways
Summary
Prenatal inflammation has been proposed as an important mediating factor in several adverse pregnancy outcomes. 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. Elevated inflammation beyond the physiological increase during pregnancy has been implicated as a mediator in the associations of a myriad of prenatal exposures (e.g., infectious disease [2], maternal obesity [3, 4], maternal stress [5], and air pollution [6]) with offspring health. Developmental programming studies suggest that prenatal exposures could alter long-term offspring health through epigenetic changes, often effected via DNA methylation. DNA methylation is one epigenetic modification that has become frequently studied due to the availability of reliable and affordable technologies
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