Molecular subtypes explain lupus epigenomic heterogeneity unveiling new regulatory genetic risk variants.
Journal
NPJ genomic medicine
ISSN: 2056-7944
Titre abrégé: NPJ Genom Med
Pays: England
ID NLM: 101685193
Informations de publication
Date de publication:
16 Jul 2024
16 Jul 2024
Historique:
received:
03
04
2023
accepted:
17
05
2024
medline:
17
7
2024
pubmed:
17
7
2024
entrez:
16
7
2024
Statut:
epublish
Résumé
The heterogeneity of systemic lupus erythematosus (SLE) can be explained by epigenetic alterations that disrupt transcriptional programs mediating environmental and genetic risk. This study evaluated the epigenetic contribution to SLE heterogeneity considering molecular and serological subtypes, genetics and transcriptional status, followed by drug target discovery. We performed a stratified epigenome-wide association studies of whole blood DNA methylation from 213 SLE patients and 221 controls. Methylation quantitative trait loci analyses, cytokine and transcription factor activity - epigenetic associations and methylation-expression correlations were conducted. New drug targets were searched for based on differentially methylated genes. In a stratified approach, a total of 974 differential methylation CpG sites with dependency on molecular subtypes and autoantibody profiles were found. Mediation analyses suggested that SLE-associated SNPs in the HLA region exert their risk through DNA methylation changes. Novel genetic variants regulating DNAm in disease or in specific molecular contexts were identified. The epigenetic landscapes showed strong association with transcription factor activity and cytokine levels, conditioned by the molecular context. Epigenetic signals were enriched in known and novel drug targets for SLE. This study reveals possible genetic drivers and consequences of epigenetic variability on SLE heterogeneity and disentangles the DNAm mediation role on SLE genetic risk and novel disease-specific meQTLs. Finally, novel targets for drug development were discovered.
Identifiants
pubmed: 39013887
doi: 10.1038/s41525-024-00420-0
pii: 10.1038/s41525-024-00420-0
doi:
Types de publication
Journal Article
Langues
eng
Pagination
38Investigateurs
Lorenzo Beretta
(L)
Barbara Vigone
(B)
Jacques-Olivier Pers
(JO)
Alain Saraux
(A)
Valérie Devauchelle-Pensec
(V)
Divi Cornec
(D)
Sandrine Jousse-Joulin
(S)
Bernard Lauwerys
(B)
Julie Ducreux
(J)
Anne-Lise Maudoux
(AL)
Carlos Vasconcelos
(C)
Ana Tavares
(A)
Esmeralda Neves
(E)
Raquel Faria
(R)
Mariana Brandão
(M)
Ana Campar
(A)
António Marinho
(A)
Fátima Farinha
(F)
Isabel Almeida
(I)
Miguel Angel Gonzalez-Gay Mantecón
(MAG)
Ricardo Blanco Alonso
(RB)
Alfonso Corrales Martínez
(AC)
Ricard Cervera
(R)
Ignasi Rodríguez-Pintó
(I)
Gerard Espinosa
(G)
Rik Lories
(R)
Ellen De Langhe
(E)
Nicolas Hunzelmann
(N)
Doreen Belz
(D)
Torsten Witte
(T)
Niklas Baerlecken
(N)
Georg Stummvoll
(G)
Michael Zauner
(M)
Michaela Lehner
(M)
Eduardo Collantes
(E)
Rafaela Ortega Castro
(RO)
Ma Angeles Aguirre-Zamorano
(MA)
Alejandro Escudero-Contreras
(A)
Ma Carmen Castro-Villegas
(MC)
Norberto Ortego
(N)
María Concepción Fernández Roldán
(MCF)
Enrique Raya
(E)
Inmaculada Jiménez Moleón
(IJ)
Enrique de Ramon
(E)
Isabel Díaz Quintero
(ID)
Pier Luigi Meroni
(PL)
Maria Gerosa
(M)
Tommaso Schioppo
(T)
Carolina Artusi
(C)
Carlo Chizzolini
(C)
Aleksandra Zuber
(A)
Donatienne Wynar
(D)
Laszló Kovács
(L)
Attila Balog
(A)
Magdolna Deák
(M)
Márta Bocskai
(M)
Sonja Dulic
(S)
Gabriella Kádár
(G)
Falk Hiepe
(F)
Velia Gerl
(V)
Silvia Thiel
(S)
Manuel Rodriguez Maresca
(MR)
Antonio López-Berrio
(A)
Rocío Aguilar-Quesada
(R)
Héctor Navarro-Linares
(H)
Montserrat Alvarez
(M)
Damiana Alvarez-Errico
(D)
Nancy Azevedo
(N)
Nuria Barbarroja
(N)
Anne Buttgereit
(A)
Qingyu Cheng
(Q)
Carlo Chizzolini
(C)
Jonathan Cremer
(J)
Aurélie De Groof
(A)
Ellen De Langhe
(E)
Julie Ducreux
(J)
Aleksandra Dufour
(A)
Velia Gerl
(V)
Maria Hernandez-Fuentes
(M)
Laleh Khodadadi
(L)
Katja Kniesch
(K)
Tianlu Li
(T)
Chary Lopez-Pedrera
(C)
Zuzanna Makowska
(Z)
Concepción Marañón
(C)
Brian Muchmore
(B)
Esmeralda Neves
(E)
Bénédicte Rouvière
(B)
Quentin Simon
(Q)
Elena Trombetta
(E)
Nieves Varela
(N)
Torsten Witte
(T)
Informations de copyright
© 2024. The Author(s).
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