{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:34:16Z","timestamp":1787027656338,"version":"build-2736575974"},"reference-count":151,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T00:00:00Z","timestamp":1772236800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Autoimmune diseases arise from complex interactions between genetic susceptibility, immune regulation, and tissue-specific inflammatory processes, yet most risk variants identified by genome-wide association studies occur in non-coding regions with poorly defined biological functions. This review addresses the challenge of interpreting non-coding regulatory variants in autoimmunity by synthesizing emerging analytical frameworks that integrate functional genomics, single-cell profiling, spatial transcriptomics, and multi-omics data. We describe stepwise strategies that refine statistical associations through regulatory annotation, immune cell\u2013state resolution, and perturbational evidence, highlighting complementary approaches such as massively parallel reporter assays, transcriptome-wide association studies, and single-cell expression quantitative trait locus mapping. These methods demonstrate that many autoimmune risk variants exert context-dependent effects that emerge only in specific immune cell states, activation trajectories, or tissue microenvironments. Advances in spatial and chromatin-informed technologies further clarify how regulatory variation shapes immune circuits in diseases such as systemic lupus erythematosus and rheumatoid arthritis. Finally, we discuss how machine learning-enabled multi-omics integration supports molecular endotyping and therapeutic inference while emphasizing interpretability and reproducibility. Collectively, this review highlights a shift from static variant annotation toward dynamic, context-aware analytical frameworks that enable mechanism-informed interpretation of genetic risk in autoimmune disease.<\/jats:p>","DOI":"10.3390\/biology15050407","type":"journal-article","created":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T16:06:59Z","timestamp":1772467619000},"page":"407","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Non-Coding Regulatory Variants in Autoimmune Disease: Biological Mechanisms, Immune Context, and Integrative Multi-Omics Interpretation"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-8516-2313","authenticated-orcid":false,"given":"Ahmed S. A.","family":"Ali Agha","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman 11942, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nawras A.","family":"Al-Zaki","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman 11942, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saif Aldeen Nasser","family":"Alshammari","sequence":"additional","affiliation":[{"name":"Fachbereich Chemie & Biologie, Hochschule Fresenius, Limburger Stra\u00dfe 2, 65510 Idstein, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lama","family":"Odeh","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa 13133, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renata","family":"Obekh","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa 13133, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nour","family":"Sameer","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman 11942, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1123-3583","authenticated-orcid":false,"given":"Hussam","family":"M. Askari","sequence":"additional","affiliation":[{"name":"School of Medicine, Jordan University of Science and Technology, Irbid 22110, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7973-0473","authenticated-orcid":false,"given":"Nancy","family":"Hakooz","sequence":"additional","affiliation":[{"name":"Department of Biopharmaceutics and Clinical Pharmacy, School of Pharmacy, University of Jordan, Amman 11942, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim","family":"Al-Adham","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Medical Sciences, University of Petra, Amman 11196, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8529-2548","authenticated-orcid":false,"given":"Phillip J.","family":"Collier","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Medical Sciences, University of Petra, Amman 11196, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.1007\/s11427-021-2187-3","article-title":"Innate and adaptive immune abnormalities underlying autoimmune diseases: The genetic connections","volume":"66","author":"Chi","year":"2023","journal-title":"Sci. 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