Castellini-Pérez Olivia, Povedano Elena, Barturen Guillermo, Martínez-Bueno Manuel, Iakovliev Andrii, Kerick Martin, López-Domínguez Raúl, Marañón Concepción, Martín Javier, Ballestar Esteban, Borghi María Orietta, Qiu Weiliang, Zhu Cheng, Shankara Srinivas, Spiliopoulou Athina, de Rinaldis Emanuele, Carnero-Montoro Elena, Alarcón-Riquelme Marta E
GENYO. Center for Genomics and Oncological Research Pfizer/University of Granada/Andalusian Regional Government, 18016, Granada, Spain.
University of Granada, Granada, Spain.
NPJ Genom Med. 2024 Jul 16;9(1):38. doi: 10.1038/s41525-024-00420-0.
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.
系统性红斑狼疮（SLE）的异质性可由表观遗传改变来解释，这些改变会破坏介导环境和遗传风险的转录程序。本研究考虑分子和血清学亚型、遗传学和转录状态，评估了表观遗传对SLE异质性的影响，随后进行了药物靶点发现。我们对213例SLE患者和221例对照的全血DNA甲基化进行了分层表观基因组范围关联研究。进行了甲基化数量性状位点分析、细胞因子和转录因子活性-表观遗传关联以及甲基化-表达相关性分析。基于差异甲基化基因寻找新的药物靶点。采用分层方法，共发现974个依赖于分子亚型和自身抗体谱的差异甲基化CpG位点。中介分析表明，HLA区域中与SLE相关的单核苷酸多态性（SNP）通过DNA甲基化变化发挥其风险作用。鉴定出在疾病或特定分子背景下调节DNA甲基化的新型遗传变异。表观遗传景观显示与转录因子活性和细胞因子水平密切相关，受分子背景影响。表观遗传信号在SLE的已知和新型药物靶点中富集。本研究揭示了表观遗传变异性对SLE异质性的可能遗传驱动因素和后果，并阐明了DNA甲基化在SLE遗传风险和新型疾病特异性甲基化数量性状位点（meQTL）中的中介作用。最后，发现了新的药物开发靶点。
