Understanding Post-translational Modifications to Circulating Histones Via Mass Spectrometry in Pregnant Women Developing Pre-eclampsia: A Retrospective Study

Study Overview
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Brief Summary
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This is a descriptive pilot study on a ready-constituted biobank (outside the Jardé Law). It is an ancillary study to the GrossPath cohort (RCB ID number: 2014-A01120-47). Pregnancy generates an increased risk of thrombosis, and placenta-mediated diseases constitute a risk factor for cardiovascular pathologies responsible for significant maternal-fetal morbidity and mortality. Understanding and exploring the cellular and molecular mechanisms of dysfunctions of the vascular-placental interface could provide arguments to understand the systemic vascular risk, characterize it and finally detect it on the basis of new markers, thus opening the way for targeted preventive management to reinforce the general principles of precision medicine. Netosis is a process of activation of neutrophils, which then generate filaments containing DNA, enzymes and extracellular histones. Netosis occurs in pregnancy and is increased in vascular-placental complications. It can be studied by measuring circulating histones, particularly the citrullinated histone H3. Levels of this modified histone H3, as well as those of two other modifications, have recently been shown to increase during pregnancy. These levels have also been shown to be even greater in pregnancy complications. The aim of this study is to complete this mapping in order to obtain a precise signature for all post-translational histone modifications in normal pregnancies and pregnancies complicated by pre-eclampsia from the GrossPath cohort in order to propose new circulating biomarkers for placental vascular pathologies. The post-translational histone modification profiles (mapping) of pregnant women with normal pregnancies will be compared with those developing pre-eclampsia.

Official Title
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A Retrospective Study Using Mass Spectrometry to Characterize Post-translational Modifications to Circulating Histones in Pregnant Women Developing Pre-eclampsia

Conditions
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Pregnancy Related, Pre-Eclampsia

Intervention / Treatment
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* Diagnostic Test: Analysis of post-translational histone modifications via mass spectrometry


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Not applicable as this study is on samples from a biobank. The inclusion criteria for the GrossPath cohort were: pregnant women followed at Nîmes University hospital for normal pregnancy or pregnancy with placental vascular pathology (pre-eclampsia and/or intra-uterine growth retardation). The patient must have given her free and informed consent and signed the consent form. The patient must be a member or beneficiary of a health insurance plan Only women are included Patients are at least 18 years old Exclusion Criteria: Not applicable as this is a study on samples from a biobank. The non-inclusion criteria of the GrossPath cohort were : twin pregnancies.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Plasma from women with normal pregnancies<br>Plasma collected from women with normal pregnancies will be analyzed by mass spectrometry | Diagnostic Test: Analysis of post-translational histone modifications via mass spectrometry<br>* During the GrossHist study (NCT04205383), only 3 post-translational histone modifications available in ELISA at the time were quantified thanks to a collaboration with the VOLITION™ company [Bouvier and Fortier et al. 2021]. The development of a new mass spectrometry approach based on nucleosome enrichment of plasma, developed by collaborators at VOLITION™, has made it possible to consider the description of all post-translational histone modifications (about 40 post-translational modifications involving histones H2A, H2B, H3 and H4).<br>|
| Plasma from women with placenta-mediated complications<br>Plasma collected from women who developed preeclampsia during pregnancy will be analyzed by mass spectrometry | Diagnostic Test: Analysis of post-translational histone modifications via mass spectrometry<br>* During the GrossHist study (NCT04205383), only 3 post-translational histone modifications available in ELISA at the time were quantified thanks to a collaboration with the VOLITION™ company [Bouvier and Fortier et al. 2021]. The development of a new mass spectrometry approach based on nucleosome enrichment of plasma, developed by collaborators at VOLITION™, has made it possible to consider the description of all post-translational histone modifications (about 40 post-translational modifications involving histones H2A, H2B, H3 and H4).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Presence of methylation in histone H2A in pregnant women with normal pregnancies | Mass spectrometry will be used to detect the presence or not of methylation in histone H2A and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of methylation in histone H2A in pregnant women developing pre-eclampsia | Mass spectrometry will be used to detect the presence or not of methylation in histone H2A and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of methylation in histone H2B in pregnant women with normal pregnancies | Mass spectrometry will be used to detect the presence or not of methylation in histone H2B and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of methylation in histone H2B in pregnant women developing pre-eclampsia | Mass spectrometry will be used to detect the presence or not of methylation in histone H2B and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of methylation in histone H3 in pregnant women with normal pregnancies | Mass spectrometry will be used to detect the presence or not of methylation in histone H3 and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of methylation in histone H3 in pregnant women developing pre-eclampsia | Mass spectrometry will be used to detect the presence or not of methylation in histone H3 and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of methylation in histone H4 in pregnant women with normal pregnancies | Mass spectrometry will be used to detect the presence or not of methylation in histone H4 and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of methylation in histone H4 in pregnant women developing pre-eclampsia | Mass spectrometry will be used to detect the presence or not of methylation in histone H4 and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of acetylation in histone H2A in pregnant women with normal pregnancies | Mass spectrometry will be used to detect the presence or not of acetylation in histone H2A and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of acetylation in histone H2A in pregnant women developing pre-eclampsia | Mass spectrometry will be used to detect the presence or not of acetylation in histone H2A and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of acetylation in histone H2B in pregnant women with normal pregnancies | Mass spectrometry will be used to detect the presence or not of acetylation in histone H2B and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of acetylation in histone H2B in pregnant women developing pre-eclampsia | Mass spectrometry will be used to detect the presence or not of acetylation in histone H2B and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of acetylation in histone H3 in pregnant women with normal pregnancies | Mass spectrometry will be used to detect the presence or not of acetylation in histone H3 and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of acetylation in histone H3 in pregnant women developing pre-eclampsia | Mass spectrometry will be used to detect the presence or not of acetylation in histone H3 and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of acetylation in histone H4 in pregnant women with normal pregnancies | Mass spectrometry will be used to detect the presence or not of acetylation in histone H4 and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of acetylation in histone H4 in pregnant women developing pre-eclampsia | Mass spectrometry will be used to detect the presence or not of acetylation in histone H4 and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of phosphorylation in histone H2A in pregnant women with normal pregnancies | Mass spectrometry will be used to detect the presence or not of phosphorylation in histone H2A and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of phosphorylation in histone H2A in pregnant women developing pre-eclampsia | Mass spectrometry will be used to detect the presence or not of phosphorylation in histone H2A and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of phosphorylation in histone H2B in pregnant women with normal pregnancies | Mass spectrometry will be used to detect the presence or not of phosphorylation in histone H2B and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of phosphorylation in histone H2B in pregnant women developing pre-eclampsia | Mass spectrometry will be used to detect the presence or not of phosphorylation in histone H2B and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of phosphorylation in histone H3 in pregnant women with normal pregnancies | Mass spectrometry will be used to detect the presence or not of phosphorylation in histone H3 and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of phosphorylation in histone H3 in pregnant women developing pre-eclampsia | Mass spectrometry will be used to detect the presence or not of phosphorylation in histone H3 and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of phosphorylation in histone H4 in pregnant women with normal pregnancies | Mass spectrometry will be used to detect the presence or not of phosphorylation in histone H4 and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of phosphorylation in histone H4 in pregnant women developing pre-eclampsia | Mass spectrometry will be used to detect the presence or not of phosphorylation in histone H4 and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of ubiquitination in histone H2A in pregnant women with normal pregnancies | Mass spectrometry will be used to detect the presence or not of ubiquitination in histone H2A and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of ubiquitination in histone H2A in pregnant women developing pre-eclampsia | Mass spectrometry will be used to detect the presence or not of ubiquitination in histone H2A and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of ubiquitination in histone H2B in pregnant women with normal pregnancies | Mass spectrometry will be used to detect the presence or not of ubiquitination in histone H2B and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of ubiquitination in histone H2B in pregnant women developing pre-eclampsia | Mass spectrometry will be used to detect the presence or not of ubiquitination in histone H2B and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of ubiquitination in histone H3 in pregnant women with normal pregnancies | Mass spectrometry will be used to detect the presence or not of ubiquitination in histone H3 and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of ubiquitination in histone H3 in pregnant women developing pre-eclampsia | Mass spectrometry will be used to detect the presence or not of ubiquitination in histone H3 and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of ubiquitination in histone H4 in pregnant women with normal pregnancies | Mass spectrometry will be used to detect the presence or not of ubiquitination in histone H4 and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of ubiquitination in histone H4 in pregnant women developing pre-eclampsia | Mass spectrometry will be used to detect the presence or not of ubiquitination in histone H4 and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of citrullination in histone H2A in pregnant women with normal pregnancies | Mass spectrometry will be used to detect the presence or not of citrullination in histone H2A and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of citrullination in histone H2A in pregnant women developing pre-eclampsia | Mass spectrometry will be used to detect the presence or not of citrullination in histone H2A and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of citrullination in histone H2B in pregnant women with normal pregnancies | Mass spectrometry will be used to detect the presence or not of citrullination in histone H2B and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of citrullination in histone H2B in pregnant women developing pre-eclampsia | Mass spectrometry will be used to detect the presence or not of citrullination in histone H2B and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of citrullination in histone H3 in pregnant women with normal pregnancies | Mass spectrometry will be used to detect the presence or not of citrullination in histone H3 and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of citrullination in histone H3 in pregnant women developing pre-eclampsia | Mass spectrometry will be used to detect the presence or not of citrullination in histone H3 and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of citrullination in histone H4 in pregnant women with normal pregnancies | Mass spectrometry will be used to detect the presence or not of citrullination in histone H4 and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 
| Presence of citrullination in histone H4 in pregnant women developing pre-eclampsia | Mass spectrometry will be used to detect the presence or not of citrullination in histone H4 and recorded as YES/NO. | At pregnancy term (max 41 weeks gestation) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intensity of methylation in histone H2A in pregnant women with normal pregnancies | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of methylation in histone H2A in pregnant women developing pre-eclampsia | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of methylation in histone H2B in pregnant women with normal pregnancies | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of methylation in histone H2B in pregnant women developing pre-eclampsia | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of methylation in histone H3 in pregnant women with normal pregnancies | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of methylation in histone H3 in pregnant women developing pre-eclampsia | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of methylation in histone H4 in pregnant women with normal pregnancies | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of methylation in histone H4 in pregnant women developing pre-eclampsia | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of acetylation in histone H2A in pregnant women with normal pregnancies | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of acetylation in histone H2A in pregnant women developing pre-eclampsia | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of acetylation in histone H2B in pregnant women with normal pregnancies | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of acetylation in histone H2B in pregnant women developing pre-eclampsia | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of acetylation in histone H3 in pregnant women with normal pregnancies | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of acetylation in histone H3 in pregnant women developing pre-eclampsia | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of acetylation in histone H4 in pregnant women with normal pregnancies | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of acetylation in histone H4 in pregnant women developing pre-eclampsia | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of phosphorylation in histone H2A in pregnant women with normal pregnancies | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of phosphorylation in histone H2A in pregnant women developing pre-eclampsia | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of phosphorylation in histone H2B in pregnant women with normal pregnancies | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of phosphorylation in histone H2B in pregnant women developing pre-eclampsia | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of phosphorylation in histone H3 in pregnant women with normal pregnancies | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of phosphorylation in histone H3 in pregnant women developing pre-eclampsia | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of phosphorylation in histone H4 in pregnant women with normal pregnancies | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of phosphorylation in histone H4 in pregnant women developing pre-eclampsia | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of ubiquitination in histone H2A in pregnant women with normal pregnancies | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of ubiquitination in histone H2A in pregnant women developing pre-eclampsia | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of ubiquitination in histone H2B in pregnant women with normal pregnancies | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of ubiquitination in histone H2B in pregnant women developing pre-eclampsia | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of ubiquitination in histone H3 in pregnant women with normal pregnancies | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of ubiquitination in histone H3 in pregnant women developing pre-eclampsia | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of ubiquitination in histone H4 in pregnant women with normal pregnancies | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of ubiquitination in histone H4 in pregnant women developing pre-eclampsia | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of citrullination in histone H2A in pregnant women with normal pregnancies | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of citrullination in histone H2A in pregnant women developing pre-eclampsia | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of citrullination in histone H2B in pregnant women with normal pregnancies | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of citrullination in histone H2B in pregnant women developing pre-eclampsia | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of citrullination in histone H3 in pregnant women with normal pregnancies | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of citrullination in histone H3 in pregnant women developing pre-eclampsia | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of citrullination in histone H4 in pregnant women with normal pregnancies | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Intensity of citrullination in histone H4 in pregnant women developing pre-eclampsia | Mass spectrometry, quantitative | At pregnancy term (max 41 weeks gestation) | 
| Presence of methylation in histone H2A in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | YES/NO | Before 34 weeks of pregnancy | 
| Presence of methylation in histone H2A in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | YES/NO | 34 to 41 weeks of pregnancy | 
| Presence of methylation in histone H2B in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | YES/NO | Before 34 weeks of pregnancy | 
| Presence of methylation in histone H2B in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | YES/NO | 34 to 41 weeks of pregnancy | 
| Presence of methylation in histone H3 in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | YES/NO | Before 34 weeks of pregnancy | 
| Presence of methylation in histone H3 in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | YES/NO | 34 to 41 weeks of pregnancy | 
| Presence of methylation in histone H4 in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | YES/NO | Before 34 weeks of pregnancy | 
| Presence of methylation in histone H4 in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | YES/NO | 34 to 41 weeks of pregnancy | 
| Presence of acetylation in histone H2A in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | YES/NO | Before 34 weeks of pregnancy | 
| Presence of acetylation in histone H2A in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | YES/NO | 34 to 41 of pregnancy | 
| Presence of acetylation in histone H2B in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | YES/NO | Before 34 weeks of pregnancy | 
| Presence of acetylation in histone H2B in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | YES/NO | 34 to 41 weeks of pregnancy | 
| Presence of acetylation in histone H3 in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | YES/NO | Before 34 weeks of pregnancy | 
| Presence of acetylation in histone H3 in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | YES/NO | After 34 weeks of pregnancy | 
| Presence of acetylation in histone H4 in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | YES/NO | Before 34 weeks of pregnancy | 
| Presence of acetylation in histone H4 in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | YES/NO | 34 to 41 weeks of pregnancy | 
| Presence of phosphorylation in histone H2A in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | YES/NO | Before 34 weeks of pregnancy | 
| Presence of phosphorylation in histone H2A in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | YES/NO | 34 to 41 weeks of pregnancy | 
| Presence of phosphorylation in histone H2B in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | YES/NO | Before 34 weeks of pregnancy | 
| Presence of phosphorylation in histone H2B in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | YES/NO | 34 to 41 weeks of pregnancy | 
| Presence of phosphorylation in histone H3 in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | YES/NO | Before 34 weeks of pregnancy | 
| Presence of phosphorylation in histone H3 in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | YES/NO | 34 to 41 weeks of pregnancy | 
| Presence of phosphorylation in histone H4 in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | YES/NO | Before 34 weeks of pregnancy | 
| Presence of phosphorylation in histone H4 in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | YES/NO | 34 to 41 weeks of pregnancy | 
| Presence of ubiquitination in histone H2A in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | YES/NO | Before 34 weeks of pregnancy | 
| Presence of ubiquitination in histone H2A in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | YES/NO | 34 to 41 weeks of pregnancy | 
| Presence of ubiquitination in histone H2B in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | YES/NO | Before 34 weeks of pregnancy | 
| Presence of ubiquitination in histone H2B in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | YES/NO | 34 to 41 weeks of pregnancy | 
| Presence of ubiquitination in histone H3 in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | YES/NO | Before 34 weeks of pregnancy | 
| Presence of ubiquitination in histone H3 in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | YES/NO | 34 to 41 weeks of pregnancy | 
| Presence of ubiquitination in histone H4 in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | YES/NO | Before 34 weeks of pregnancy | 
| Presence of ubiquitination in histone H4 in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | YES/NO | 34 to 41 weeks of pregnancy | 
| Presence of citrullination in histone H2A in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | YES/NO | Before 34 weeks of pregnancy | 
| Presence of citrullination in histone H2A in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | YES/NO | 34 to 41 weeks of pregnancy | 
| Presence of citrullination in histone H2B in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | YES/NO | Before 34 weeks of pregnancy | 
| Presence of citrullination in histone H2B in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | YES/NO | 34 to 41 weeks of pregnancy | 
| Presence of citrullination in histone H3 in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | YES/NO | Before 34 weeks of pregnancy | 
| Presence of citrullination in histone H3 in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | YES/NO | 34 to 41 weeks of pregnancy | 
| Presence of citrullination in histone H4 in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | YES/NO | Before 34 weeks of pregnancy | 
| Presence of citrullination in histone H4 in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | YES/NO | 34 to 41 weeks of pregnancy | 
| Intensity of methylation in histone H2A in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | Mass spectrometry, quantitative | Before 34 weeks of pregnancy | 
| Intensity of methylation in histone H2A in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | Mass spectrometry, quantitative | 34 to 41 weeks of pregnancy | 
| Intensity of methylation in histone H2B in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | Mass spectrometry, quantitative | Before 34 weeks of pregnancy | 
| Intensity of methylation in histone H2B in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | Mass spectrometry, quantitative | 34 to 41 weeks of pregnancy | 
| Intensity of methylation in histone H3 in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | Mass spectrometry, quantitative | Before 34 weeks of pregnancy | 
| Intensity of methylation in histone H3 in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | Mass spectrometry, quantitative | 34 to 41 weeks of pregnancy | 
| Intensity of methylation in histone H4 in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | Mass spectrometry, quantitative | Before 34 weeks of pregnancy | 
| Intensity of methylation in histone H4 in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | Mass spectrometry, quantitative | 34 to 41 weeks of pregnancy | 
| Intensity of acetylation in histone H2A in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | Mass spectrometry, quantitative | Before 34 weeks of pregnancy | 
| Intensity of acetylation in histone H2A in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | Mass spectrometry, quantitative | 34 to 41 weeks of pregnancy | 
| Intensity of acetylation in histone H2B in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | Mass spectrometry, quantitative | Before 34 weeks of pregnancy | 
| Intensity of acetylation in histone H2B in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | Mass spectrometry, quantitative | 34 to 41 weeks of pregnancy | 
| Intensity of acetylation in histone H3 in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | Mass spectrometry, quantitative | Before 34 weeks of pregnancy | 
| Intensity of acetylation in histone H3 in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | Mass spectrometry, quantitative | 34 to 41 weeks of pregnancy | 
| Intensity of acetylation in histone H4 in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | Mass spectrometry, quantitative | Before 34 weeks of pregnancy | 
| Intensity of acetylation in histone H4 in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | Mass spectrometry, quantitative | 34 to 41 weeks of pregnancy | 
| Intensity of phosphorylation in histone H2A in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | Mass spectrometry, quantitative | Before 34 weeks of pregnancy | 
| Intensity of phosphorylation in histone H2A in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | Mass spectrometry, quantitative | 34 to 41 weeks of pregnancy | 
| Intensity of phosphorylation in histone H2B in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | Mass spectrometry, quantitative | Before 34 weeks of pregnancy | 
| Intensity of phosphorylation in histone H2B in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | Mass spectrometry, quantitative | 34 to 41 weeks of pregnancy | 
| Intensity of phosphorylation in histone H3 in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | Mass spectrometry, quantitative | Before 34 weeks of pregnancy | 
| Intensity of phosphorylation in histone H3 in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | Mass spectrometry, quantitative | 34 to 41 weeks of pregnancy | 
| Intensity of phosphorylation in histone H4 in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | Mass spectrometry, quantitative | Before 34 weeks of pregnancy | 
| Intensity of phosphorylation in histone H4 in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | Mass spectrometry, quantitative | 34 to 41 weeks of pregnancy | 
| Intensity of ubiquitination in histone H2A in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | Mass spectrometry, quantitative | Before 34 weeks of pregnancy | 
| Intensity of ubiquitination in histone H2A in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | Mass spectrometry, quantitative | 34 to 41 weeks of pregnancy | 
| Intensity of ubiquitination in histone H2B in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | Mass spectrometry, quantitative | Before 34 weeks of pregnancy | 
| Intensity of ubiquitination in histone H2B in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | Mass spectrometry, quantitative | 34 to 41 of pregnancy | 
| Intensity of ubiquitination in histone H3 in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | Mass spectrometry, quantitative | Before 34 weeks of pregnancy | 
| Intensity of ubiquitination in histone H3 in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | Mass spectrometry, quantitative | 34 to 41 weeks of pregnancy | 
| Intensity of ubiquitination in histone H4 in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | Mass spectrometry, quantitative | Before 34 weeks of pregnancy | 
| Intensity of ubiquitination in histone H4 in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | Mass spectrometry, quantitative | 34 to 41 weeks of pregnancy | 
| Intensity of citrullination in histone H2A in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | Mass spectrometry, quantitative | Before 34 weeks of pregnancy | 
| Intensity of citrullination in histone H2A in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | Mass spectrometry, quantitative | 34 to 41 weeks of pregnancy | 
| Intensity of citrullination in histone H2B in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | Mass spectrometry, quantitative | Before 34 weeks of pregnancy | 
| Intensity of citrullination in histone H2B in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | Mass spectrometry, quantitative | 34 to 41 weeks of pregnancy | 
| Intensity of citrullination in histone H3 in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | Mass spectrometry, quantitative | Before 34 weeks of pregnancy | 
| Intensity of citrullination in histone H3 in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | Mass spectrometry, quantitative | 34 to 41 weeks of pregnancy | 
| Intensity of citrullination in histone H4 in pregnant women developing pre-eclampsia before 34 weeks of pregnancy | Mass spectrometry, quantitative | Before 34 weeks of pregnancy | 
| Intensity of citrullination in histone H4 in pregnant women developing pre-eclampsia after 34 weeks of pregnancy | Mass spectrometry, quantitative | 34 to 41 weeks of pregnancy | 
| Modifications in histones H2A, H2B, H3 and H4 in women developing pre-eclampsia early on compared with modifications in histones H2A, H2B, H3 and H4 in women with normal pregnancies. | The presence of methylation, acetylation, phosphorylation, ubiquitination and citrullination in each histone in women developing pre-eclampsia early on will be recorded as YES/NO. | Before 34 weeks of pregnancy | 
| Modifications in histones H2A, H2B, H3 and H4 in women developing pre-eclampsia later on compared with modifications in histones H2A, H2B, H3 and H4 in women with normal pregnancies. | The presence of methylation, acetylation, phosphorylation, ubiquitination and citrullination in each histone in women developing pre-eclampsia later on will be recorded as YES/NO. | 34 to 41 weeks of pregnancy | 
| Intensity of modifications in histones H2A, H2B, H3 and H4 in women developing pre-eclampsia early on compared with modifications in histones H2A, H2B, H3 and H4 in women with normal pregnancies. | Mass spectrometry, quantitative | Before 34 weeks of pregnancy | 
| Intensity of modifications in histones H2A, H2B, H3 and H4 in women developing pre-eclampsia later on compared with modifications in histones H2A, H2B, H3 and H4 in women with normal pregnancies. | Mass spectrometry, quantitative | 34 to 41 weeks of pregnancy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pregnancy, Pre-eclampsia, Histones, Mass spectrometry, Neutrophils, Extracellular traps