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While DNA methylation changes have been implicated in SLE pathogenesis, their relationship to disease activity remains unclear. This study aimed to identify epigenetic correlates of disease activity in women with SLE using genome-wide DNA methylation profiling. Whole blood DNA from 48 women with established SLE was analyzed using Illumina EPIC arrays. Disease activity was assessed using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K). Differentially methylated positions (DMPs) and regions (DMRs) associated with disease activity were identified using linear modeling and region-level analyses, adjusting for age, ethnicity, smoking status, body mass index (BMI), and cell composition. Gene ontology enrichment and motif analyses were also performed. No individual CpGs reached FDR-corrected significance, therefore, a hypothesis-generating approach using a raw\n                    <jats:italic>p<\/jats:italic>\n                    -value\u2009&lt;\u20090.01 was applied. Over 4,500 suggestive DMPs (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01) were identified and further analyzed for DMRs and pathway mapping. Thirty-six significant DMRs (at 1% false discovery rate) were detected, with several genes involved in neuroimmune regulation and systemic inflammation. Motif analysis identified REST, a transcriptional repressor that silences neuronal genes in non-neuronal tissues, as a common motif among several DMRs. Semantic analysis of the affected loci revealed five major biological domains relevant to SLE: immune signaling, neuroimmune and neural processes, organ developmental morphogenesis, metabolic regulation, and epigenetic control. This exploratory study identified potential epigenome-wide methylation changes linked to disease activity in a well-controlled cohort of women with SLE. Region-level analysis revealed DMRs mapping to immune and neuroimmune pathways and showed enrichment of the REST binding motif. Although these findings are preliminary and require independent validation, they suggest subtle epigenetic alterations that may be associated with SLE activity and points to candidate pathways for further investigation.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-51708-3","type":"journal-article","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T18:34:51Z","timestamp":1778006091000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Epigenome-wide DNA methylation patterns associated with disease activity in systemic lupus erythematosus"],"prefix":"10.1038","volume":"16","author":[{"given":"Amin","family":"Ravaei","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tahzeeb","family":"Fatima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Wincup","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Rudin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Maglio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Bjersing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,5]]},"reference":[{"key":"51708_CR1","unstructured":"Justiz Vaillant, A.A., Goyal, A., Varacallo, M.A. Systemic Lupus Erythematosus. 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