EPIGENETIC PROFILING OF CHILDHOOD-ONSET LUPUS REVEALS DISTINCT EPIGENETIC CLUSTERS AND SUGGESTS EPIGENETIC DRIVERS OF DISEASE ACTIVITY
Bibliographic record
Abstract
PV110 / #608 Poster Topic: AS12 - Genetics, Epigenetics, Transcriptomics Background/Purpose Systemic lupus erythematosus, or lupus, is a chronic autoimmune disease that can affect multiple organ systems. Childhood-onset lupus is typically associated with a more severe disease course compared to adult-onset lupus. DNA methylation alterations play an important role in the pathogenesis of lupus. We have previously demonstrated a higher genetic risk for lupus in childhood-onset compared to adult-onset disease. However, epigenetic studies in childhood-onset lupus have been limited. The aim of this study was to investigate DNA methylation changes in childhood-onset lupus. Methods A total of 64 patients with childhood-onset lupus and 47 healthy controls from Turkey were included in this study. DNA from peripheral blood mononuclear cells (PBMCs) was isolated to assess DNA methylation patterns using the Infinium MethylationEPIC v2.0 array (Illumina). Quality controls and statistical analyses were performed using minfi and limma R packages. Methylation differences among groups were tested through linear regression, adjusting for age, sex, medication use, and cell subset compositions. Differences in clinical manifestations were assessed using Fisher’s exact tests. Gene ontology (GO) enrichment analyses were performed with the online tools Metascape and GREAT. Results Case-control differential DNA methylation analysis revealed significant hypomethylation in interferon-regulated genes, such as DTX3L, PARP9, IFI44L , and MX1 , in patients compared to controls. The enrichment analysis confirmed the presence of type I interferon signature-related biological processes, consistent with our previous findings in adult-onset lupus. The association of DNA methylation levels and disease activity in lupus, as measured by SLEDAI scores, revealed progressive hypomethylation in genes related to B cell activation and cellular senescence as the disease becomes more active. K-means clustering analysis of lupus patients based on DNA methylation patterns identified 3 distinct lupus clusters. Cluster 1 was characterized by the enrichment of hypomethylated genes involved in cell adhesion and response to growth factor pathways; Cluster 2 exhibited hypomethylation in genes related to regulation of cell differentiation and cell fate determination; and Cluster 3 showed enrichment in response to oxidative stress and Rap1 signaling pathway in hypomethylated genes. Conclusions We identified significant hypomethylation in interferon-regulated genes, consistent with the type I interferon epigenetic signature observed in adult-onset lupus. Furthermore, the relationship between DNA methylation changes and disease activity, particularly in genes associated with B cell activation and cellular senescence, suggests that these alterations may play a role in disease progression. The identification of distinct DNA methylation clusters also underscores the heterogeneity of childhood-onset lupus, offering potential avenues for personalized therapeutic strategies. These findings emphasize the need for further investigation into the epigenetic mechanisms driving childhood-onset lupus to improve diagnosis and treatment approaches.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.004 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".