{"doi":"10.1101/2022.02.21.22271293","title":"Hypomethylation of miR-17-92 cluster in lupus T cells and no significant role for genetic factors in the lupus-associated DNA methylation signature","abstract":"Abstract Objectives Epigenetic dysregulation plays an important role in the pathogenesis of lupus, a systemic autoimmune disease characterized by autoantibody production. Lupus T cells demonstrate aberrant DNA methylation patterns dominated by hypomethylation of interferon-regulated genes. The objective of this study was to identify additional disease-associated DNA methylation changes in naïve CD4+ T cells from an extended cohort of lupus patients and determine the genetic contribution to epigenetic changes characteristic of lupus. Methods Genome-wide DNA methylation was assessed in naïve CD4+ T cells isolated from a cohort of 74 lupus patients and 74 age-, sex-, and race-matched healthy controls. We applied a trend deviation analysis approach, comparing methylation data in our cohort to methylation data from over 16,500 samples to characterize lupus-associated DNA methylation patterns. Methylation quantitative trait loci (meQTL) analysis was used to determine genetic contribution to lupus-associated DNA methylation changes. Results In addition to the previously reported epigenetic signature in interferon-regulated genes, we observed hypomethylation of the promoter regions of microRNA (miRNA) genes in the miR-17-92 cluster in lupus patients. Members of this miRNA cluster play an important role in regulating T cell proliferation and differentiation. Expression of two miRNAs within this cluster, miR-19b1 and miR-18a, showed a significant positive correlation with disease activity in lupus patients. meQTL were identified by integrating genome-wide DNA methylation profiles with genotyping data in lupus patients and controls. Patient meQTL show overlap with genetic risk loci for lupus. However, less than 1% of differentially methylated CpG sites in lupus patients were associated with an meQTL, suggesting minimal genetic contribution to lupus-associated epigenotypes. Conclusion The lupus defining epigenetic signature, characterized by robust hypomethylation of interferon-regulated genes, does not appear to be determined by genetic factors. Hypomethylation of the miR-17-92 cluster that plays an important role in T cell activation is a novel epigenetic locus for lupus.","journal":"medRxiv","year":2022,"id":302712,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9503,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":649716,"name":"Xiavan Roopnarinesingh","orcid":"0000-0003-2530-1478","position":1,"is_corresponding":false},{"id":314475,"name":"Lourdes Ortiz‐Fernández","orcid":"0000-0002-0247-4280","position":2,"is_corresponding":false},{"id":314477,"name":"Kathleen Maksimowicz‐McKinnon","orcid":"0000-0001-8839-9906","position":3,"is_corresponding":false},{"id":314476,"name":"Emily E. Lewis","orcid":"0000-0001-5721-0787","position":4,"is_corresponding":false},{"id":240897,"name":"Joan T. Merrill","orcid":"0000-0002-4514-2382","position":5,"is_corresponding":false},{"id":315994,"name":"W. Joseph McCune","orcid":null,"position":6,"is_corresponding":false},{"id":355806,"name":"Jonathan D. Wren","orcid":"0000-0003-2776-3545","position":7,"is_corresponding":false},{"id":235896,"name":"Amr H. Sawalha","orcid":"0000-0002-3884-962X","position":8,"is_corresponding":false},{"id":237109,"name":"Patrick Coit","orcid":"0000-0003-0660-764X","position":0,"is_corresponding":true}],"reference_count":77,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:32:20.348385Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}