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Integrative epigenomics in Sjögren´s syndrome reveals novel pathways and a strong interaction between the HLA, autoantibodies and the interferon signature

María Teruel 1 Guillermo Barturen 1 Manuel Martínez-Bueno 1 Olivia Castellini-Pérez 1 Miguel Barroso-Gil 1 Elena Povedano 1 Martin Kerick 2 Francesc Català-Moll 3, 4 Zuzanna Makowska 5 Anne Buttgereit 5 Jacques-Olivier Pers 6 Concepción Marañón 1 Esteban Ballestar 3, 4 Javier Martin 2 Elena Carnero-Montoro 1 Marta Alarcón-Riquelme 1 Lorenzo Beretta 7 Barbara Vigone 7 Alain Saraux 6, 8 Valérie Devauchelle-Pensec 6, 8 Divi Cornec 6, 8 Sandrine Jousse-Joulin 6, 8 Bernard Lauwerys 9 Julie Ducreux 10 Anne-Lise Maudoux 11 Carlos Vasconcelos 12 Ana Tavares 13 Esmeralda Neves 14 Raquel Faria 14 Mariana Brandão 15 Ana Campar 15 António Marinho 15 Fátima Farinha 16 Isabel Almeida 16 Miguel Angel Gonzalez-Gay Mantecón 17 Ricardo Blanco Alonso 17 Alfonso Corrales Martínez 18 Ricard Cervera 19 Ignasi Rodríguez-Pintó 19 Gerard Espinosa 19 Rik Lories 20 Ellen de Langhe 20 Nicolas Hunzelmann 21 Doreen Belz 21 Torsten Witte 22 Niklas Baerlecken 23 Georg Stummvoll 24 Michael Zauner 24 Michaela Lehner Eduardo Collantes 25 Rafaela Ortega-Castro 26 Mª Angeles Aguirre-Zamorano 27 Alejandro Escudero-Contreras 27 Mª Carmen Castro-Villegas 27 Norberto Ortego 28 María Concepción Fernández Roldán 27 Enrique Raya 29 Inmaculada Jiménez Moleón 29 Enrique de Ramon 30 Isabel Díaz Quintero 30 Pier Luigi Meroni 31 Maria Gerosa 31 Tommaso Schioppo 31 Carolina Artusi 31 Carlo Chizzolini 32 Aleksandra Zuber 32 Donatienne Wynar 32 Laszló Kovács 33 Attila Balog 33 Magdolna Deák 33 Márta Bocskai 33 Sonja Dulic 33 Gabriella Kádár 33 Falk Hiepe 34 Velia Gerl 34 Silvia Thiel 34 Manuel Rodriguez Maresca 35 Antonio López-Berrio 35 Rocío Aguilar-Quesada 35 Héctor Navarro-Linares 35 Montserrat Alvarez 32 Damiana Alvarez‑errico 4 Nancy Azevedo 27 Nuria Barbarroja 27 Qingyu Cheng 34 Jonathan Cremer 11 Aurélie de Groof 36 Aleksandra Dufour 32 Maria Hernandez‑fuentes Laleh Khodadadi 37 Katja Kniesch 38 Tianlu Li 39 Chary Lopez‑pedrera 40 Brian Muchmore Bénédicte Rouvière 6 Quentin Simon 6 Elena Trombetta 41 Nieves Varela 42
Abstract : Abstract Primary Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study, we confirmed a vast coordinated hypomethylation and overexpression effects in IFN-related genes, what is known as the IFN signature. Stratified and conditional analyses suggest a strong interaction between SS-associated HLA genetic variation and the presence of Anti-Ro/SSA autoantibodies in driving the IFN epigenetic signature and determining SS. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified potential new genetic variants associated with SS that might mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, autoantibody profiles, DNA methylation and gene expression in SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune population.
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https://hal.univ-brest.fr/hal-03533050
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Submitted on : Tuesday, January 18, 2022 - 4:08:19 PM
Last modification on : Friday, April 22, 2022 - 11:42:06 AM

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María Teruel, Guillermo Barturen, Manuel Martínez-Bueno, Olivia Castellini-Pérez, Miguel Barroso-Gil, et al.. Integrative epigenomics in Sjögren´s syndrome reveals novel pathways and a strong interaction between the HLA, autoantibodies and the interferon signature. Scientific Reports, Nature Publishing Group, 2021, 11 (1), pp.23292. ⟨10.1038/s41598-021-01324-0⟩. ⟨hal-03533050⟩

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