Integrative epigenomics in Sjögren´s syndrome reveals novel pathways and a strong interaction between the HLA, autoantibodies and the interferon signature
Authors: Teruel María , Barturen Guillermo , Martínez-Bueno Manuel , Castellini-Pérez Olivia , Barroso-Gil Miguel , Povedano Elena , Kerick Martin , Català-Moll Francesc , Makowska Zuzanna , Buttgereit Anne ,   PRECISESADS 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 , Ortega-Castro Rafaela , 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 ,   PRECISESADS 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 , Pers Jacques-Olivier , Marañón Concepción , Ballestar Esteban , Martin Javier , Carnero-Montoro Elena , Alarcón-Riquelme Marta E. 
Published: December 2021

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-associatedHLAgenetic 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.