Integrative epigenomics in Sjögren´s syndrome reveals novel pathways and a strong interaction between the HLA, autoantibodies and the interferon signature
María Teruel, Guillermo Barturen, Manuel Martínez‐Bueno, Olivia Castellini-Pérez, Miguel Barroso‐Gil, Elena Povedano, Martin Kerick, Francesc Català‐Moll, Zuzanna Makowska, Anne Buttgereit, Lorenzo Beretta, Barbara Vigone, Jacques‐Olivier Pers, Alain Saraux, Valérie Devauchelle‐Pensec, Divi Cornec, Sandrine Jousse‐Joulin, Bernard Lauwerys, Julie Ducreux, Anne‐Lise Maudoux, Carlos Vasconcelos, Ana Tavares, Esmeralda Neves, Raquel Faria, Mariana Brandão, Ana Campar, António Marinho, Fátima Farinha, Isabel Almeida, Miguel Á. González‐Gay, Ricardo Blanco, Alfonso Corrales Martínez, Ricard Cervera, Ignasi Rodríguez‐Pintó, Gerard Espinosa, Rik Lories, Ellen De Langhe, Nicolas Hunzelmann, Doreen Belz, Torsten Witte, N.T. Baerlecken, Georg Stummvoll, Michael Zauner, Michaela Lehner, Eduardo Collantes‐Estévez, R. Ortega Castro, M. Á. Aguirre, Alejandro Escudero‐Contreras, Ma Carmen Castro‐Villegas, N. Ortego, María Concepción Fernández Roldán, Enrique Raya, Inmaculada Jiménez Moleón, Enrique de Ramón, Isabel Díaz Quintero, Pier Luigi Meroni, Maria Gerosa, Tommaso Schioppo, Carolina Artusi, Carlo Chizzolini, Aleksandra Zuber, Donatienne Wynar, László Kovács, Attila Balog, Magdolna Deák, Márta Bocskai, Sonja Dulic, Gabriella Kádár, Falk Hiepe, Velia Gerl, Silvia Thiel, Manuel Rodríguez Maresca, Antonio López‐Berrio, Rocío Aguilar‐Quesada, Héctor Navarro‐Linares, PRECISESADS Flow Cytometry Study Group, Montserrat Alvarez, Damiana Álvarez‐Errico, Nancy Azevedo, Nuria Barbarroja, Anne Buttgereit, Qingyu Cheng, Carlo Chizzolini, Jonathan Cremer, Aurélie De Groof, Ellen De Langhe, Julie Ducreux, Aleksandra Maria Dufour, Velia Gerl, María P. Hernández-Fuentes, Laleh Khodadadi, Katja Kniesch, Tianlu Li, C. López-Pedrera, Zuzanna Makowska, Concepción Marañón, Brian Muchmore, Esmeralda Neves, Bénédicte Rouvière, Quentin Simon
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.