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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

1 GENYO - Centre for Genomics and Oncological Research Pfizer [Granada, Spain]

2 IPBLN - Instituto de Parasitología y Biomedicina “López-Neyra”

3 Epigenetics and Immune Disease Group, Josep Carreras Research Institute (IJC), 08916 Badalona, Barcelona, Spain

4 IDIBELL - Institut d'Investigació Biomèdica de Bellvitge [Barcelone]

5 Pharmaceuticals Division Bayer Pharma Aktiengesellschaft

6 LBAI - Lymphocytes B, Autoimmunité et Immunothérapies

7 University of Milan, Fondazione IRCCS Policlinico Milano

8 CHU - BREST - Rhumato - CHRU Brest - Service de Rhumatologie

9 Service de Rhumatologie, CHU Brugmann

10 IREC - Institut de Recherche Expérimentale et Clinique

11 UCL - Université Catholique de Louvain = Catholic University of Louvain

12 Universidade Federal de Pernanbuco

13 Hospital da Policia Militar de Minas Gerais

14 Unidade de Imunologia Clínica, Centro Hospitalar do Porto, Portugal

15 ICBAS - Instituto de Ciências Biomédicas de Abel Salazar

16 Centro Hospitalar do Porto

17 Hospital Universitario Marqués de Valdecilla [Santander]

18 IDIVAL - Marqués de Valdecilla Research Institute - Instituto de Investigación Marqués de Valdecilla [Santander]

19 Department of Medicine - Autoimmune Diseases Unit, Barcelona

20 Division of Rheumatology at University Hospitals Leuven and of the Department of Development and Regeneration at KU Leuven

21 University Hospital of Cologne [Cologne]

22 MHH, Medical University of Hannover

23 Kooperatives Rheumazentrum Aachen-Köln-Bonn Laboratory

24 INSTITUTE OF IMMUNOLOGY, MEDICAL UNIVERSITY OF VIENNA - Institute of Immunology Medical University of Vienna

25 Universidad de Córdoba = University of Córdoba [Córdoba]

26 2. M3C-Necker, Hôpital universitaire Necker-Enfants malades, Université de Paris, Paris, France

27 IMIBIC - Instituto Maimonides de Investigación Biomédica de Cordoba

28 University of Granada [Granada]

29 Hospitales Universitarios de Granada/Universidad de Granada

30 Hospital Regional Universitario de Málaga = Regional University Hospital of Malaga [Spain]

31 University di Milano - UNiversity di Milano

32 HUG - Hôpital Universitaire de Genève = University Hospitals of Geneva

33 University of Szeged [Szeged]

34 Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]

35 Andalusian School of Public Health [Granada]

36 CSIC - Spanish National Research Council

37 DRFZ - Leibniz Institute - German Rheumatism Research Centre

38 Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico [Milan, Italy]

39 IMIDOMICS Inc Barcelona

40 University Hospitals Leuven [Leuven]

41 Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico

42 University of Veterinary Medicine [Hannover]

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.

Document type :

Journal articles

Domain :

Life Sciences [q-bio] / Immunology

Complete list of metadata

https://hal.univ-brest.fr/hal-03533050
Contributor : Geneviève Michel Connect in order to contact the contributor
Submitted on : Tuesday, January 18, 2022 - 4:08:19 PM
Last modification on : Tuesday, November 29, 2022 - 5:10:07 PM