TY - JOUR
T1 - Molecular subtypes explain lupus epigenomic heterogeneity unveiling new regulatory genetic risk variants
AU - PRECISEADS Clinical Consortium
AU - , PRECISEADS Flow Cytometry Study Group
AU - Castellini-Pérez, Olivia
AU - Povedano, Elena
AU - Barturen, Guillermo
AU - Martinez-Bueno, Manuel
AU - Iakovliev, Andrii
AU - Kerick, Martin
AU - Marañón, Concepción
AU - Martin, Javier
AU - Ballestar, Esteban
AU - Orietta Borghi, María
AU - Qiu, Weiliang
AU - Zhu, Cheng
AU - Shankara, Srinivas
AU - Spiliopoulou, Athina
AU - de Rinaldis, Emanuele
AU - Carnero-Montoro, Elena
AU - Alarcon-Riquelme, Marta E.
PY - 2024/7/16
Y1 - 2024/7/16
N2 - 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.
AB - 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.
U2 - 10.1038/s41525-024-00420-0
DO - 10.1038/s41525-024-00420-0
M3 - Article
SN - 2056-7944
VL - 9
JO - npj Genomic Medicine
JF - npj Genomic Medicine
M1 - 38
ER -