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 Medizinische Universität Wien = 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 UGR - Universidad de Granada = University of 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 - Hôpitaux universitaires 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 - Consejo Superior de Investigaciones Cientificas = 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]
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 Medizinische Universität Wien = 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 UGR - Universidad de Granada = University of 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 - Hôpitaux universitaires 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 - Consejo Superior de Investigaciones Cientificas = 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]
Jacques-Olivier Pers
- Function : Author
- PersonId : 753610
- IdHAL : jacques-olivier-pers
- ORCID : 0000-0001-7287-5541
- IdRef : 068262159
Alain Saraux
- Function : Author
- PersonId : 762362
- ORCID : 0000-0002-8454-7067
Valérie Devauchelle-Pensec
- Function : Author
- PersonId : 766858
- ORCID : 0000-0003-0432-825X
Divi Cornec
- Function : Author
- PersonId : 766860
- ORCID : 0000-0002-9159-702X
Sandrine Jousse-Joulin
- Function : Author
- PersonId : 766854
- ORCID : 0000-0002-5479-5887
Michaela Lehner
- Function : Author
Carlo Chizzolini
- Function : Author
- PersonId : 767598
- ORCID : 0000-0003-4849-6335
Maria Hernandez‑fuentes
- Function : Author
Brian Muchmore
- Function : Author
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.