Integrative epigenomics in Sjögren´s syndrome reveals novel pathways and a strong interaction between the HLA, autoantibodies and the interferon signature Teruel Artacho, María Barturen Briñas, Guillermo Martínez Bueno, Manuel Castellini Pérez, Olivia Barroso Gil, Miguel Povedano Espejo, Elena Kerick, Martin Marañón Lizana, Concepción Martín Ibáñez, Javier Carnero Montoro, Elena Alarcón Riquelme, Marta Eugenia Castro Villegas, Mª Carmen Ortego Centeno, Norberto Fernández Roldán, María Concepción Raya Álvarez, Enrique Germán Jiménez Moleón, Inmaculada Rodríguez Maresca, Manuel López Berrio, Antonio Aguilar Quesada, Rocío Navarro Linares, Héctor Muchmore, Brian PRECISESADS Clinical Consortium PRECISESADS Flow Cytometry Study Group Funding for the preparation of this manuscript has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115,565, resources composed of the financial contribution from the European Union's Seventh Framework Program (FP7/2007-2013) and the EFPIA companies' in kind contribution. MT is supported by a Spanish grant from Health Department, Junta de Andalucia (PI/0017/2016) and through the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 806975. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA. EC-M was funded by the Postdoctoral Training Subprogramme Juan de la Cierva-Ministry of Economy and Competitiveness (FJCI_2014_20652). We thank Ralf Lesche for the production of RNASeq data and Marc Torres Ciuro for design support. 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. 2022-01-12T08:11:07Z 2022-01-12T08:11:07Z 2021-12-02 info:eu-repo/semantics/article Teruel, M... [et al.]. Integrative epigenomics in Sjögren´s syndrome reveals novel pathways and a strong interaction between the HLA, autoantibodies and the interferon signature. Sci Rep 11, 23292 (2021). [https://doi.org/10.1038/s41598-021-01324-0] http://hdl.handle.net/10481/72314 10.1038/s41598-021-01324-0 eng info:eu-repo/grantAgreement/EC/H2020/806975 http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess Atribución 3.0 España Nature