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

NCT05142410 | Completed

• 1 other identifier: NIMAO/2021-1/SB01
• Study Type: observational
• Target: 28
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Pregnancy Related; Pre-Eclampsia

Keywords

Pregnancy; Pre-eclampsia; Histones; Mass spectrometry; Neutrophils; Extracellular traps

Outcome Measures

Primary Outcomes (40)

• 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 Outcomes (124)

• Intensity of methylation in histone H2A in pregnant women with normal pregnancies

  At pregnancy term (max 41 weeks gestation)

• Intensity of methylation in histone H2A in pregnant women developing pre-eclampsia

  At pregnancy term (max 41 weeks gestation)

• Intensity of methylation in histone H2B in pregnant women with normal pregnancies

  At pregnancy term (max 41 weeks gestation)

• Intensity of methylation in histone H2B in pregnant women developing pre-eclampsia

  At pregnancy term (max 41 weeks gestation)

• Intensity of methylation in histone H3 in pregnant women with normal pregnancies

  At pregnancy term (max 41 weeks gestation)

Study Arms (2)

Plasma from women with normal pregnancies

Plasma collected from women with normal pregnancies will be analyzed by mass spectrometry

Diagnostic Test: Analysis of post-translational histone modifications via mass spectrometry

Plasma from women with placenta-mediated complications

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

Interventions

Analysis of post-translational histone modifications via mass spectrometry DIAGNOSTIC_TEST

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).

Plasma from women with normal pregnancies; Plasma from women with placenta-mediated complications

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: The study is based on frozen plasma samples from pregnant women, taken at the time of them giving birth from among the 50 women who constituted the GrossPath cohort. Fourteen of these women had had normal pregnancies and fourteen had developed pre-eclampsia. Cases are matched on maternal age, clinical event (delivery) and gestational age will be included from the GrossPath cohort.
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

The study is based on frozen plasma samples from pregnant women, taken at the time of them giving birth from among the 50 women who constituted the GrossPath cohort. Fourteen of these women had had normal pregnancies and fourteen had developed pre-eclampsia. Cases are matched on maternal age, clinical event (delivery) and gestational age will be included from the GrossPath cohort.

You may qualify if:

• 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

You may not qualify if:

• twin pregnancies.

Sponsors & Collaborators

• Centre Hospitalier Universitaire de Nīmes: lead

Study Sites (1)

Nîmes University Hospital

Nîmes, Gard, 30900, France

Location

Biospecimen

Retention: SAMPLES WITH DNA

This study is based on the mass spectrometric analysis of frozen plasma samples from patients included in the "GrossPath" cohort (BCR ID: 2014-A01120-47). The benefits will ultimately be a better understanding of the physiopathological mechanisms involved in the occurrence of this placental vascular pathology.

MeSH Terms

Conditions

Pre-Eclampsia

Condition Hierarchy (Ancestors)

Hypertension, Pregnancy-Induced; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases

Study Officials

• Sylvie BOUVIER, Dr.

  Nîmes University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 18, 2021
• First Posted: December 2, 2021
• Study Start: March 1, 2019
• Primary Completion: November 30, 2020
• Study Completion: December 1, 2023
• Last Updated: January 31, 2024

Record last verified: 2024-01

Locations

FR (1)