Targeted resequencing reveals rare variants enrichment in multiple sclerosis susceptibility genes.

B-Lymphocytes Case-Control Studies DNA Mutational Analysis Genetic Predisposition to Disease Humans Leukocytes, Mononuclear Membrane Proteins / genetics Multiple Sclerosis / genetics RGS Proteins / genetics Spain TNF Receptor-Associated Factor 3 / genetics Vitamin D3 24-Hydroxylase / genetics
RGS1 interferon-β multiple sclerosis rare variants single nucleotide polymorphisms targeted DNA sequencing

Journal

Human mutation
ISSN: 1098-1004
Titre abrégé: Hum Mutat
Pays: United States
ID NLM: 9215429

Informations de publication

Date de publication:
07 2020
Historique:
received: 17 06 2019
revised: 05 03 2020
accepted: 18 03 2020
pubmed: 21 3 2020
medline: 6 11 2021
entrez: 21 3 2020
Statut: ppublish

Résumé

Although genome-wide association studies have identified a number of common variants associated with multiple sclerosis (MS) susceptibility, little is known about the relevance of rare variants. Here, we aimed to explore the role of rare variants in 14 MS risk genes (FCRL1, RGS1, TIMMDC1, HHEX, CXCR5, LTBR, TSFM, GALC, TRAF3, STAT3, TNFSF14, IFI30, CD40, and CYP24A1) by targeted resequencing in an Iberian population of 524 MS cases and 546 healthy controls. Four rare variants-enriched regions within CYP24A1, FCRL1, RGS1, and TRAF3 were identified as significantly associated with MS. Functional studies revealed significantly decreased regulator of G protein signaling 1 (RGS1) gene expression levels in peripheral blood mononuclear cells from MS patients with RGS1 rare variants compared to noncarriers, whereas no significant differences in gene expression were observed for CYP24A1, FCRL1, and TRAF3 between rare variants carriers and noncarriers. Immunophenotyping showed significant decrease in RGS1 expression in peripheral blood B lymphocytes from MS patients with RGS1 rare variants relative to noncarriers. Lastly, peripheral blood mononuclear cell from MS patients carrying RGS1 rare variants showed significantly lower induction of RGS1 gene expression by interferon-β compared to MS patients lacking RGS1 variants. The presence of rare variants in RGS1 reinforce the ideas of high genetic heterogeneity and a role of rare variants in MS pathogenesis.

Identifiants

DOI: 10.1002/humu.24016 PMID: 32196808
pubmed: 32196808
doi: 10.1002/humu.24016
doi:

Substances chimiques

FCRL1 protein, human 0
Membrane Proteins 0
RGS Proteins 0
RGS1 protein, human 0
TNF Receptor-Associated Factor 3 0
TRAF3 protein, human 0
CYP24A1 protein, human EC 1.14.15.16
Vitamin D3 24-Hydroxylase EC 1.14.15.16

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1308-1320

Informations de copyright

© 2020 Wiley Periodicals, Inc.

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Auteurs

Elia Gil-Varea (E)

Servei de Neurologia-Neuroimmunologia, Center d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.

Nino Spataro (N)

Genetics Laboratory, UDIAT-Centre Diagnòstic, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain.

Luisa María Villar (LM)

Departments of Immunology and Neurology, Multiple Sclerosis Unit, Hospital Ramon y Cajal, (IRYCIS), Madrid, Spain.

Amalia Tejeda-Velarde (A)

Departments of Immunology and Neurology, Multiple Sclerosis Unit, Hospital Ramon y Cajal, (IRYCIS), Madrid, Spain.

Luciana Midaglia (L)

Servei de Neurologia-Neuroimmunologia, Center d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.

Fuencisla Matesanz (F)

Department of Cell Biology and Immunology, Instituto de Parasitología y Biomedicina "López Neyra", Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Granada, Spain.

Sunny Malhotra (S)

Servei de Neurologia-Neuroimmunologia, Center d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.

Herena Eixarch (H)

Servei de Neurologia-Neuroimmunologia, Center d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.

Nikolaos Patsopoulos (N)

Department of Neurology, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Óscar Fernández (Ó)

Neuroimmunology and Neuroinflammation Group, Instituto de Investigación Biomédica de Málaga-IBIMA. UGC Neurociencias, Hospital Regional Universitario de Málaga, Málaga, Spain.

Begoña Oliver-Martos (B)

Neuroimmunology and Neuroinflammation Group, Instituto de Investigación Biomédica de Málaga-IBIMA. UGC Neurociencias, Hospital Regional Universitario de Málaga, Málaga, Spain.

Albert Saiz (A)

Servicio de Neurología, Hospital Clinic and Institut d'Investigació Biomèdica Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Sara Llufriu (S)

Servicio de Neurología, Hospital Clinic and Institut d'Investigació Biomèdica Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Lluís Ramió-Torrentà (L)

Department of Medical Sciences, Faculty of Medicine, Neurodegeneration and Neuroinflammation Group, Girona Biomedical Research Institute (IdIBGi), University of Girona, Girona, Spain.

Ester Quintana (E)

Department of Medical Sciences, Faculty of Medicine, Neurodegeneration and Neuroinflammation Group, Girona Biomedical Research Institute (IdIBGi), University of Girona, Girona, Spain.

Guillermo Izquierdo (G)

Departamento de Neurología, Hospital Universitario Virgen Macarena, Sevilla, Spain.

Antonio Alcina (A)

Department of Cell Biology and Immunology, Instituto de Parasitología y Biomedicina "López Neyra", Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Granada, Spain.

Elena Bosch (E)

Genetics Laboratory, UDIAT-Centre Diagnòstic, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain.
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Reus, Spain.

Arcadi Navarro (A)

Genetics Laboratory, UDIAT-Centre Diagnòstic, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain.
Centre de Regulació Genòmica (CRG), Barcelona, España.
Institució Catalana de Recerca i Estudis Avançats (ICREA), Cataluña, Spain.

Xavier Montalban (X)

Servei de Neurologia-Neuroimmunologia, Center d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.

Manuel Comabella (M)

Servei de Neurologia-Neuroimmunologia, Center d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
ORCID: 0000-0002-2373-6657

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Classifications MeSH

questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Leucocytes › Agranulocytes › Lymphocytes › Lymphocytes B › Targeted resequencing reveals rare variants...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études cas-témoins › Targeted resequencing reveals rare variants...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de séquence › Analyse de séquence d'ADN › Analyse de mutations d'ADN › Targeted resequencing reveals rare variants...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › Targeted resequencing reveals rare variants...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Targeted resequencing reveals rare variants...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Leucocytes › Agranulocytes › Targeted resequencing reveals rare variants...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Targeted resequencing reveals rare variants...
questionsmedicales.fr › Maladies du système immunitaire › Maladies auto-immunes › Maladies auto-immunes du système nerveux › Maladies démyélinisantes auto-immunes du SNC › Sclérose en plaques › Targeted resequencing reveals rare variants...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Régulateurs des protéines G › Protéines d'activation de la GTPase › Protéines RGS › Targeted resequencing reveals rare variants...
questionsmedicales.fr › Régions géographiques › Europe › Espagne › Targeted resequencing reveals rare variants...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines adaptatrices de la transduction du signal › Protéines et peptides associés aux récepteurs des facteurs de nécrose tumorale › Facteur-3 associé aux récepteurs de TNF › Targeted resequencing reveals rare variants...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Hémoprotéines › Cytochromes › Cytochrome P-450 enzyme system › Famille-24 de cytochromes P450 › Vitamine D3 24-hydroxylase › Targeted resequencing reveals rare variants...