Neurogenetics and Multi-omics of Neuroinflammatory Diseases in Multiplex Families to Improve Patients Health (NeuroDIP)
The goal of this observational study is to learn why some families have several members with multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), or MOG antibody-associated disease (MOGAD). These diseases happen when the immune system attacks the brain, optic nerves, or spinal cord. The study includes about 500 people from about 100 families: people with one of these diseases and their relatives who do not have it. The main question is: Do rare gene changes (variants) shared by family members explain why these diseases run in families? Researchers will compare the DNA of family members who have the disease with the DNA of relatives who do not. They will also look at how genes are switched on and off in blood cells. Participants will:
- Attend one visit of 2 to 3 hours at one of five French hospitals
- Answer questions about their health, treatments, and family history
- Give a 50 mL blood sample
Tutkimuksen yleiskatsaus
Tila
Ehdot
Interventio / Hoito
Yksityiskohtainen kuvaus
Background: Large genetic studies have found many common gene variants that raise the risk of multiple sclerosis, but they explain only part of the inherited risk. They also explain familial forms poorly. Rare variants with a strong effect may be shared within a family and go unnoticed in studies of unrelated people. Families with several affected members are well suited to finding them. NeuroDIP combines genetic, epigenetic (DNA methylation), and gene expression data from these families and links them to clinical information.
Design: This is a cross-sectional, family-based study with a single visit and no follow-up. Comparing affected members with unaffected relatives from the same family helps limit the effect of ancestry and of factors that relatives share.
Visit: At the hospital, participants give written consent and have a short physical examination. Patients also have a disability assessment (EDSS). The investigator draws a family tree and records medical history, treatments, lifestyle, and any previous brain MRI report. A blood sample is then drawn. The study does not change usual medical care. Relatives are invited through the affected family member and are contacted by the investigating centre.
Samples and data: Samples and data carry a code, and names are kept only at the investigating centre. Samples are processed and stored in accredited biological resource centres. Research data are stored on secure servers in France and are not transferred outside the European Union. With participants' consent, coded data and samples may be used in future research on neuroinflammatory diseases, including deposit in the French MS registry (OFSEP).
Results: Participants do not receive individual research results. The exception is an incidental finding with health consequences, and participants must agree to be informed of such a finding before they take part. Participants can ask for the overall results and may be invited to an optional information meeting for families.
Funding: The study is funded by the Inserm Messidore 2024 call and by the ARSEP Foundation, and belongs to the NeuroDINet network on neuroinflammatory diseases.
Opintotyyppi
Ilmoittautuminen (Arvioitu)
Vaihe
- Ei sovellettavissa
Yhteystiedot ja paikat
Opiskeluyhteys
- Nimi: David Axel LAPLAUD, MD PhD
- Puhelinnumero: +33 240165176
- Sähköposti: david.laplaud@chu-nantes.fr
Tutki yhteystietojen varmuuskopiointi
- Nimi: Nicolas VINCE, PhD
- Puhelinnumero: +33 253526229
- Sähköposti: nicolas.vince@univ-nantes.fr
Opiskelupaikat
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-
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Bron, Ranska, 69500
- Hospice Civil de Lyon - Hospital Pierre Wertheimer
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Ottaa yhteyttä:
- Sandra VUKUSIC
- Puhelinnumero: +33 04 72 68 13 13
- Sähköposti: sandra.vukusic@chu-lyon.fr
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Päätutkija:
- Sandra Vukusic
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Nantes, Ranska, 44000
- University Hospital Laennec
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Päätutkija:
- David-Axel LAPLAUD
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Ottaa yhteyttä:
- David-Axel LAPLAUD
- Puhelinnumero: +33 02 40 16 52 00
- Sähköposti: david.laplaud@chu-nantes.fr
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Nice, Ranska, 06002
- University Hospital Pasteur 2
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Päätutkija:
- Christine LEBRUN-FRENAY
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Ottaa yhteyttä:
- Christine LEBRUN-FRENAY
- Puhelinnumero: +33 04 92 03 71 00
- Sähköposti: lebrun-frenay.c@chu-nice.fr
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Paris, Ranska, 75013
- Assistance Publique Hôpitaux de Paris- La Pitié Salpêtrière Hospital
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Ottaa yhteyttä:
- Céline a LOUAPRE
- Puhelinnumero: +33 01 42 16 57 66
- Sähköposti: celine.louapre@aphp.fr
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Päätutkija:
- Céline LOUAPRE
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Rennes, Ranska, 35000
- University Hospital Pontchaillou
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Päätutkija:
- Laure MICHEL
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Ottaa yhteyttä:
- Laure MICHEL
- Puhelinnumero: +33 02 99 28 42 66
- Sähköposti: laure.michel@chu-rennes.fr
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Osallistumiskriteerit
Kelpoisuusvaatimukset
Opintokelpoiset iät
Hyväksyy terveitä vapaaehtoisia
Sukupuolet, jotka voivat opiskella
Kuvaus
Inclusion Criteria:
-
Affected participants:
- Age 15 years and 3 months or older
- Multiple sclerosis (2024 McDonald criteria), neuromyelitis optica spectrum disorder with anti-AQP4 antibodies (2015 Wingerchuk criteria), or MOG antibody-associated disease (2023 international MOGAD panel criteria)
- Member of a multiplex family: at least two affected members sharing at least 12.5% of their genetic heritage
- Affiliated to a social security scheme or equivalent
- Written informed consent (for minors: assent of the minor and consent of the holders of parental authority)
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Unaffected relatives:
- Age 18 years or older
- Sharing at least 25% of genetic heritage with one of the two affected family members
- No multiple sclerosis, NMOSD, MOGAD, or other known inflammatory disease of the central nervous system
- Affiliated to a social security scheme or equivalent
- Written informed consent
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Transcriptomic sub-cohort (30 to 60 participants, about 10 families):
- Patients with no immunomodulatory or immunosuppressive treatment for at least 12 months, and their relatives
Exclusion Criteria:
- Refusal to participate before the inclusion visit
- Inability to understand the study information or to consent
- Person under guardianship, curatorship or legal protection
- Person deprived of liberty by judicial or administrative decision
- Pregnant or breastfeeding woman
- No kinship with at least one affected member of the included family
- Refusal to be informed of an incidental discovery of a pathogenic genetic variant
Opintosuunnitelma
Miten tutkimus on suunniteltu?
Suunnittelun yksityiskohdat
- Ensisijainen käyttötarkoitus: Perustiede
- Jako: Ei käytössä
- Inventiomalli: Yksittäinen ryhmätehtävä
- Naamiointi: Ei mitään (avoin tarra)
Aseet ja interventiot
Osallistujaryhmä / Arm |
Interventio / Hoito |
|---|---|
|
Muut: Multiplex family members (patients and relatives)
Four participant categories (people with MS, NMOSD, MOGAD, and healthy) with their approximate numbers. |
One venous blood sample (50 mL) is drawn at a single visit. DNA is used for whole-genome sequencing. Cryopreserved peripheral blood mononuclear cells (PBMCs) are used for DNA methylation profiling and RNA sequencing. Serum is used to measure GFAP and NfL. |
Mitä tutkimuksessa mitataan?
Ensisijaiset tulostoimenpiteet
Tulosmittaus |
Toimenpiteen kuvaus |
Aikaikkuna |
|---|---|---|
|
Rare high-penetrance variants co-segregating with disease within multiplex families.
Aikaikkuna: 36 months from the first inclusion.
|
Proportion of rare (minor allele frequency < 1%), high-penetrance variants found in affected members and absent or significantly less frequent in unaffected relatives of the same family sharing at least 25% of their genetic heritage. Assessed by co-segregation and linkage analysis, family-based association tests and in silico prediction of variant impact. |
36 months from the first inclusion.
|
Toissijaiset tulostoimenpiteet
Tulosmittaus |
Toimenpiteen kuvaus |
Aikaikkuna |
|---|---|---|
|
eQTL: genetic loci associated with gene expression in PBMC
Aikaikkuna: 36 months from the first inclusion.
|
Loci where genetic variants are associated with differences in gene expression in peripheral blood mononuclear cells (PBMC), from integrated whole genome sequencing and RNA sequencing data, in the untreated patient sub-group and their relatives. |
36 months from the first inclusion.
|
|
Disease-associated DNA methylation (CpG sites)
Aikaikkuna: 36 months from the first inclusion.
|
Number and type of CpG sites differentially methylated between patients and unaffected relatives, measured with EPIC arrays on PBMC DNA, in the untreated patient sub-group and their relatives. |
36 months from the first inclusion.
|
|
Transcriptomic signatures of PBMC subpopulations
Aikaikkuna: 36 months from the first inclusion.
|
Differentially expressed genes and perturbed pathways in immune cell subpopulations, from bulk and single-cell RNA sequencing of PBMC, comparing untreated patients (dedicated sub-cohort, n = 30 to 60) with their unaffected relatives. |
36 months from the first inclusion.
|
|
Multi-omic molecular signatures
Aikaikkuna: 36 months from the first inclusion.
|
Molecular signatures obtained by integrating genomic, DNA methylation and transcriptomic data (omicsNPC framework, multilevel modelling), used to model familial risk. |
36 months from the first inclusion.
|
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Evaluation of the correlation with the disease phenotype
Aikaikkuna: 36 months from the first inclusion.
|
A potential correlation will be evaluated between genetic variants, DNA methylation, gene expression profiles and clinical data (age at onset , disease course, treatment response ) of patient. |
36 months from the first inclusion.
|
Yhteistyökumppanit ja tutkijat
Tutkijat
- Päätutkija: Nicolas VINCE, PhD, Nantes Université
Julkaisuja ja hyödyllisiä linkkejä
Yleiset julkaisut
- International Multiple Sclerosis Genetics Consortium. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science. 2019 Sep 27;365(6460):eaav7188. doi: 10.1126/science.aav7188.
- Horjus J, van Mourik-Banda T, Heerings MAP, Hakobjan M, De Witte W, Heersema DJ, Jansen AJ, Strijbis EMM, de Jong BA, Slettenaar AEJ, Zeinstra EMPE, Hoogervorst ELJ, Franke B, Kruijer W, Jongen PJ, Visser LJ, Poelmans G. Whole Exome Sequencing in Multi-Incident Families Identifies Novel Candidate Genes for Multiple Sclerosis. Int J Mol Sci. 2022 Sep 28;23(19):11461. doi: 10.3390/ijms231911461.
- Wannaphut C, Ongphichetmetha T, Satiraphan P, Jitprapaikulsan J, Apiwattanakul M, Siritho S, Prayoonwiwat N, Savangned P, Rattanathamsakul N. Familial neuromyelitis optica spectrum disorders: Case series and systematic review. Mult Scler Relat Disord. 2023 May;73:104627. doi: 10.1016/j.msard.2023.104627. Epub 2023 Mar 21.
Opintojen ennätyspäivät
Opi tärkeimmät päivämäärät
Opiskelun aloitus (Arvioitu)
Ensisijainen valmistuminen (Arvioitu)
Opintojen valmistuminen (Arvioitu)
Opintoihin ilmoittautumispäivät
Ensimmäinen lähetetty
Ensimmäinen toimitettu, joka täytti QC-kriteerit
Ensimmäinen Lähetetty (Todellinen)
Tutkimustietojen päivitykset
Viimeisin päivitys julkaistu (Todellinen)
Viimeisin lähetetty päivitys, joka täytti QC-kriteerit
Viimeksi vahvistettu
Lisää tietoa
Tähän tutkimukseen liittyvät termit
Avainsanat
Muita asiaankuuluvia MeSH-ehtoja
- Aivojen sairaudet
- Keskushermoston sairaudet
- Hermoston sairaudet
- Patologiset prosessit
- Autoimmuunisairaudet
- Immuunijärjestelmän sairaudet
- Tulehdus
- Silmäsairaudet
- Hermoston autoimmuunisairaudet
- Demyelinisoivat sairaudet
- Myeliitti, poikittainen
- Optinen neuriitti
- Näköhermon sairaudet
- Kraniaalihermoston sairaudet
- Leukoenkefalopatiat
- Patologiset tilat, merkit ja oireet
- Neuroinflammatoriset sairaudet
- Multippeliskleroosi
- Optica neuromyelitis
- Demyelinisoivat autoimmuunisairaudet, keskushermosto
- Myeliini-oligodendrosyyttiryskoproteiiniavasta-aineeseen liittyvä sairaus
- Tutkintatekniikat
- Näytteenkäsittely
- Kliiniset laboratoriotekniikat
- Diagnostiikkatekniikat ja menettelyt
- Diagnoosi
- Puhkaisut
- Kirurgiset toimenpiteet, operatiivinen
- Verinäytteen kokoelma
Muut tutkimustunnusnumerot
- C25-79
- 2026-A01125-46 (Rekisterin tunniste: IDRCB)
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