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

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.

Prenatal medication exposure and epigenetic outcomes: a systematic literature review and recommendations for prenatal pharmacoepigenetic studies

“…The DNAm of one CpG (3,500 base pairs upstream of the POU4F1 promoter) in cord blood was significantly associated with prenatal exposure to acetylsalicylic acid [30]. However, Yeung et al concluded that the association of prenatal acetylsalicylic acid exposure with DNAm in cord blood is negligible, as only one CpG with a minor effect size (1% increase in CpG DNAm) was discovered in their association study [30].…”

“…Although the studies report vastly different numbers of significant CpGs, both Gervin et al [35] and Addo et al [48] concluded that prenatal paracetamol exposure may be associated with DNAm in cord blood from susceptible individuals or placentae, respectively. Yeung et al [30] investigated the association between prenatal acetylsalicylic acid exposure and DNAm in cord blood. In the randomized controlled trial, women were randomly assigned to receive 81 mg of acetylsalicylic acid or placebo every day until conception (within six menstrual cycles) and during pregnancy [49].…”

“…In the randomized controlled trial, women were randomly assigned to receive 81 mg of acetylsalicylic acid or placebo every day until conception (within six menstrual cycles) and during pregnancy [49]. The DNAm of one CpG (3,500 base pairs upstream of the POU4F1 promoter) in cord blood was significantly associated with prenatal exposure to acetylsalicylic acid [30]. However, Yeung et al concluded that the association of prenatal acetylsalicylic acid exposure with DNAm in cord blood is negligible, as only one CpG with a minor effect size (1% increase in CpG DNAm) was discovered in their association study [30].…”

“…All of the eligible articles were based on data from single birth cohorts, except for one study validating results in an independent cohort [29], and one study being a randomized controlled trial [30] Cardenas et al (2019), who also collected blood from children aged 3-5 y and 7-11 y [29]. All studies adjusted for potential covariates and/or confounders in their statistical analyses or by design, but the number of variables under consideration differed greatly (Supplementary Table S3).…”

Neonatal Levels of Acute Phase Proteins and Risk of Autism Spectrum Disorder

“…n a l P r e -p r o o f serum and cord blood samples (48-51,54,55). In studies of paired mothers and neonates, cord blood levels of CRP were associated with DNA methylation changes in genes relevant to inflammation and angiogenesis in the neonate while maternal levels measured at multiple points over the course of pregnancy were not associated with DNA methylation in the neonate, implying that fetal levels of CRP were of particular relevance to epigenetic programming in comparison to maternal levels(55). We consider APP in NDBS as specific indicators of the neonatal innate immune status.CRP is a pattern recognition molecule, opsonin, and activator of the complement pathway(42).…”