Molecular subtypes explain lupus epigenomic heterogeneity unveiling new regulatory genetic risk variants
Authors: Castellini-Pérez Olivia , Povedano Elena , Barturen Guillermo , Martínez-Bueno Manuel , Iakovliev Andrii , Kerick Martin , López-Domínguez Raúl , Marañón Concepción , Martín Javier , Ballestar Esteban ,   PRECISEADS Clinical Consortium, Beretta Lorenzo , Vigone Barbara , Pers Jacques‐Olivier , Saraux Alain , Devauchelle‐Pensec Valérie , Cornec Divi , Jousse‐Joulin Sandrine , Lauwerys Bernard , Ducreux Julie , Maudoux Anne‐Lise , Vasconcelos Carlos , Tavares Ana , Neves Esmeralda , Faria Raquel , Brandão Mariana , Campar Ana , Marinho António , Farinha Fátima , Almeida Isabel , Mantecón Miguel Angel Gonzalez‐Gay , Alonso Ricardo Blanco , Martínez Alfonso Corrales , Cervera Ricard , Rodríguez‐Pintó Ignasi , Espinosa Gerard , Lories Rik , De Langhe Ellen , Hunzelmann Nicolas , Belz Doreen , Witte Torsten , Baerlecken Niklas , Stummvoll Georg , Zauner Michael , Lehner Michaela , Collantes Eduardo , Castro Rafaela Ortega , Aguirre‐Zamorano Ma Angeles , Escudero‐Contreras Alejandro , Castro‐Villegas Ma Carmen , Ortego Norberto , Roldán María Concepción Fernández , Raya Enrique , Moleón Inmaculada Jiménez , de Ramon Enrique , Quintero Isabel Díaz , Meroni Pier Luigi , Gerosa Maria , Schioppo Tommaso , Artusi Carolina , Chizzolini Carlo , Zuber Aleksandra , Wynar Donatienne , Kovács Laszló , Balog Attila , Deák Magdolna , Bocskai Márta , Dulic Sonja , Kádár Gabriella , Hiepe Falk , Gerl Velia , Thiel Silvia , Maresca Manuel Rodriguez , López‐Berrio Antonio , Aguilar‐Quesada Rocío , Navarro‐Linares Héctor ,   PRECISEADS Flow Cytometry Study Group, Alvarez Montserrat , Alvarez‐Errico Damiana , Azevedo Nancy , Barbarroja Nuria , Buttgereit Anne , Cheng Qingyu , Chizzolini Carlo , Cremer Jonathan , De Groof Aurélie , De Langhe Ellen , Ducreux Julie , Dufour Aleksandra , Gerl Velia , Hernandez‐Fuentes Maria , Khodadadi Laleh , Kniesch Katja , Li Tianlu , Lopez‐Pedrera Chary , Makowska Zuzanna , Marañón Concepción , Muchmore Brian , Neves Esmeralda , Rouvière Bénédicte , Simon Quentin , Trombetta Elena , Varela Nieves , Witte Torsten , Borghi María Orietta , Qiu Weiliang , Zhu Cheng , Shankara Srinivas , Spiliopoulou Athina , de Rinaldis Emanuele , Carnero-Montoro Elena , Alarcón-Riquelme Marta E. 
Published: July 2024

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.