Molecular subtypes explain lupus epigenomic heterogeneity unveiling new regulatory genetic risk variants
Castellini-Pérez, Olivia (Universidad de Granada)
Povedano, Elena (Universidad Autónoma de Madrid)
Barturen, Guillermo (Universidad de Granada)
Martínez-Bueno, Manuel (Universidad de Granada)
Iakovliev, Andrii (University of Edinburgh Medical School)
Kerick, Martin (Consejo Superior de Investigaciones Científicas (Espanya))
López-Domínguez, Raúl (Universidad de Granada)
Marañón, Concepción (Universidad de Granada)
Martín, Javier (Consejo Superior de Investigaciones Científicas (Espanya))
Ballestar, Esteban (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Borghi, María Orietta (Università degli Studi di Milano and Istituto Auxologico Italiano)
Qiu, Weiliang (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Zhu, Cheng (R&D. Sanofi, Precision Medicine & Computational Biology (Cambridge, Estats Units d'Amèrica))
Shankara, Srinivas (R&D. Sanofi, Precision Medicine & Computational Biology (Cambridge, Estats Units d'Amèrica))
Spiliopoulou, Athina (University of Edinburgh Medical School)
de Rinaldis, Emanuele (R&D. Sanofi, Precision Medicine & Computational Biology (Cambridge, Estats Units d'Amèrica))
Carnero-Montoro, Elena (University of Granada)
Alarcón-Riquelme, Marta E (Karolinska Institutet. Institute for Environmental Medicine)

Data:	2024
Resum:	The heterogeneity of systemic lupus erythematosus (SLE) can be explained by epigenetic alterations that disrupt transcriptional programs mediating environmental and genetic risk. This study evaluated the epigenetic contribution to SLE heterogeneity considering molecular and serological subtypes, genetics and transcriptional status, followed by drug target discovery. We performed a stratified epigenome-wide association studies of whole blood DNA methylation from 213 SLE patients and 221 controls. Methylation quantitative trait loci analyses, cytokine and transcription factor activity - epigenetic associations and methylation-expression correlations were conducted. New drug targets were searched for based on differentially methylated genes. In a stratified approach, a total of 974 differential methylation CpG sites with dependency on molecular subtypes and autoantibody profiles were found. Mediation analyses suggested that SLE-associated SNPs in the HLA region exert their risk through DNA methylation changes. Novel genetic variants regulating DNAm in disease or in specific molecular contexts were identified. The epigenetic landscapes showed strong association with transcription factor activity and cytokine levels, conditioned by the molecular context. Epigenetic signals were enriched in known and novel drug targets for SLE. This study reveals possible genetic drivers and consequences of epigenetic variability on SLE heterogeneity and disentangles the DNAm mediation role on SLE genetic risk and novel disease-specific meQTLs. Finally, novel targets for drug development were discovered.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	DNA methylation ; Molecular medicine
Publicat a:	npj genomic medicine, Vol. 9 (july 2024) , ISSN 2056-7944

DOI: 10.1038/s41525-024-00420-0
PMID: 39013887

13 p, 3.2 MB

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Documents de recerca > Documents dels grups de recerca de la UAB > Centres i grups de recerca (producció científica) > Ciències de la salut i biociències > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Institut de Recerca contra la Leucèmia Josep Carreras
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