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CpG methylation patterns in placenta and neonatal blood are differentially associated with neonatal inflammation

Abstract

Background

Infants born extremely premature are at increased risk for health complications later in life for which neonatal inflammation may be a contributing biological driver. Placental CpG methylation provides mechanistic information regarding the relationship between prenatal epigenetic programming, prematurity, neonatal inflammation, and later-in-life health.

Methods

We contrasted CpG methylation in the placenta and neonatal blood spots in relation to neonatal inflammation in the Extremely Low Gestational Age Newborn (ELGAN) cohort. Neonatal inflammation status was based on the expression of six inflammation-related proteins, assessed as (1) day-one inflammation (DOI) or (2) intermittent or sustained systemic inflammation (ISSI, inflammation on ≥2 days in the first 2 postnatal weeks). Epigenome-wide CpG methylation was assessed in 354 placental samples and 318 neonatal blood samples.

Results

Placental CpG methylation displayed the strongest association with ISSI (48 CpG sites) but was not associated with DOI. This was in contrast to CpG methylation in blood spots, which was associated with DOI (111 CpG sites) and not with ISSI (one CpG site).

Conclusions

Placental CpG methylation was strongly associated with ISSI, a measure of inflammation previously linked to later-in-life cognitive impairment, while day-one neonatal blood methylation was associated with DOI.

Impact

  • Neonatal inflammation increases the risk of adverse later-life outcomes, especially in infants born extremely preterm.

  • CpG methylation in the placenta and neonatal blood spots were evaluated in relation to neonatal inflammation assessed via circulating proteins as either (i) day-one inflammation (DOI) or (ii) intermittent or sustained systemic inflammation (ISSI, inflammation on ≥2 days in the first 2 weeks).

  • Tissue specificity was observed in epigenetic–inflammatory relationships: placental CpG methylation was associated with ISSI, neonatal blood CpG methylation was associated with DOI.

  • Supporting the placental origins of disease framework, placental epigenetic patterns are associated with a propensity for ISSI in neonates.

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Fig. 1: Manhattan plots showing the results of EWAS models identifying CpG methylation sites in the placenta associated with neonatal inflammation (DOI or ISSI).
Fig. 2
Fig. 3: Manhattan plots showing the results of EWAS models identifying CpG methylation sites in day-one neonatal blood spots associated with neonatal inflammation (DOI or ISSI).
Fig. 4

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Funding

This work was funded in part by the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) (R01-HD092374) and Office of The Director, National Institutes of Health (OD) (UH3-OD023348).

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Substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data: L.A.E., A.E.E., H.H., K.R., L.S., K.C.K.K., T.M.O., R.C.F. Drafting the article or revising it critically for important intellectual content: L.A.E., A.E.E., M.C., S.G., W.A.G., W.M.J., E.J., R.M.J., C.J.M., K.R., H.S., J.S.S., D.Y., K.C.K.K., T.M.O., R.C.F. Final approval of the version to be published: L.A.E., A.E.E., M.C., S.G., W.A.G., H.H., W.M.J., E.J., R.M.J., C.J.M., K.R., H.S., J.S.S., L.S., D.Y., K.C.K.K., T.M.O., R.C.F. The authors would like to acknowledge Drs. Raina Fichorova and Doug Ruden for their important contributions to this work.

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Correspondence to Rebecca C. Fry.

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Eaves, L.A., Enggasser, A.E., Camerota, M. et al. CpG methylation patterns in placenta and neonatal blood are differentially associated with neonatal inflammation. Pediatr Res (2022). https://doi.org/10.1038/s41390-022-02150-4

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