期刊
BMC MEDICINE
卷 20, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s12916-022-02610-y
关键词
Placenta; DNA methylation; Blood pressure; Pregnancy; Cell-type heterogeneity; Mesenchymal stromal cells; Epigenome-wide association study
资金
- French National Cancer Institute (INCa)
- French Institute for Public Health Research (IreSP) [INCa_13641]
- French Agency for National Research [ANR-13-CESA-0011, ANR-18-CE36-0005]
- Fondation de France [2012-00031593, 2012-00031617]
- Foundation for Medical Research (FRM)
- National Agency for Research (ANR)
- National Institute for Research in Public Health (IRESP: TGIR cohorte sante 2008 program)
- French Ministry of Health (DGS)
- French Ministry of Research, Inserm Bone and Joint Diseases National Research (PRO-A)
- Human Nutrition National Research Programs, Paris-Sud University
- Nestle
- French National Institute for Population Health Surveillance (InVS)
- French National Institute for Health Education (INPES)
- European Union
- Diabetes National Research Program (French Association of Diabetic Patients (AFD))
- ANSES
- Mutuelle Generale de l'Education Nationale (MGEN)
- French National Agency for Food Security
- Frenchspeaking Association for the Study of Diabetes and Metabolism (ALFEDIAM)
- Agence Nationale de la Recherche (ANR) [ANR-18-CE36-0005, ANR-13-CESA-0011] Funding Source: Agence Nationale de la Recherche (ANR)
This study investigated the association between placental DNA methylation patterns and maternal blood pressure during pregnancy. The results showed that maternal steady blood pressure was directly associated with placental DNA methylation levels, partly explained by changes in cell-type composition. These findings may indicate molecular mechanisms linking maternal hypertension to lung development and early origins of childhood respiratory problems, highlighting the importance of controlling maternal blood pressure during pregnancy.
Background Maternal blood pressure levels reflect cardiovascular adaptation to pregnancy and proper maternal-fetal exchanges through the placenta and are very sensitive to numerous environmental stressors. Maternal hypertension during pregnancy has been associated with impaired placental functions and with an increased risk for children to suffer from cardiovascular and respiratory diseases later on. Investigating changes in placental DNA methylation levels and cell-type composition in association with maternal blood pressure could help elucidate its relationships with placental and fetal development. Methods Taking advantage of a large cohort of 666 participants, we investigated the association between epigenome-wide DNA methylation patterns in the placenta, measured using the Infinium HumanMethylation450 BeadChip, placental cell-type composition, estimated in silico, and repeated measurements of maternal steady and pulsatile blood pressure indicators during pregnancy. Results At the site-specific level, no significant association was found between maternal blood pressure and DNA methylation levels after correction for multiple testing (false discovery rate < 0.05), but 5 out of 24 previously found CpG associations were replicated (p-value < 0.05). At the regional level, our analyses highlighted 64 differentially methylated regions significantly associated with at least one blood pressure component, including 35 regions associated with mean arterial pressure levels during late pregnancy. These regions were found enriched for genes implicated in lung development and diseases. Further mediation analyses show that a significant part of the association between steady blood pressure-but not pulsatile pressure-and placental methylation can be explained by alterations in placental cell-type composition. In particular, elevated blood pressure levels are associated with a decrease in the ratio between mesenchymal stromal cells and syncytiotrophoblasts, even in the absence of preeclampsia. Conclusions This study provides the first evidence that the association between maternal steady blood pressure during pregnancy and placental DNA methylation is both direct and partly explained by changes in cell-type composition. These results could hint at molecular mechanisms linking maternal hypertension to lung development and early origins of childhood respiratory problems and at the importance of controlling maternal blood pressure during pregnancy.
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