{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T05:25:35Z","timestamp":1765344335283,"version":"3.46.0"},"reference-count":22,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T00:00:00Z","timestamp":1765152000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease strongly influenced by genetic factors. Genome-wide association studies (GWASs) have identified numerous non-coding susceptibility loci, but their functional roles remain poorly understood. The single-nucleotide variant (SNV) rs2836882, located in an enhancer near the ETS2 proto-oncogene, has been implicated in immune regulation, though its contribution to SLE is unclear. Methods: We analyzed rs2836882 in 246 Italian patients with SLE and 216 matched controls using TaqMan genotyping. A weighted genetic risk score (wGRS) combining rs2836882 with other known SLE variants was calculated. ETS2 mRNA expression was quantified by RT-qPCR in PBMCs from 60 individuals, and in silico analyses assessed the variant\u2019s functional context. Results: The rs2836882 risk allele was significantly associated with SLE (OR = 1.54, p = 0.02). Patients showed a markedly higher wGRS than controls (p &lt; 0.00001), confirming an additive genetic burden. In silico data indicated that rs2836882 lies within an active enhancer region (H3K4me1\/H3K27ac+) containing PU.1 binding motifs and functions as an expression quantitative trait locus (eQTL) for ETS2. Expression analysis demonstrated that carriers of the risk allele exhibited significantly increased ETS2 expression compared to non-carriers (p = 0.002) in both groups. Conclusions: In conclusion, rs2836882 is a functional regulatory variant that enhances ETS2 transcription and contributes to increased SLE susceptibility. These findings establish a mechanistic link between a non-coding GWAS locus and disease risk, emphasizing the role of regulatory variants in autoimmune pathogenesis and supporting the integration of functional non-coding variants into genetic risk models for improved patient stratification.<\/jats:p>","DOI":"10.3390\/genes16121462","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T10:35:51Z","timestamp":1765190151000},"page":"1462","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["An ETS2 Enhancer Variant May Modulate Gene Expression and Contribute to Defining a Genetic Risk Profile for SLE Susceptibility"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5350-7361","authenticated-orcid":false,"given":"Andrea","family":"Latini","sequence":"first","affiliation":[{"name":"UniCamillus, Saint Camillus International University of Health Sciences, 00131 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giada","family":"De Benedittis","sequence":"additional","affiliation":[{"name":"Department of Biomedicine and Prevention, Genetics Section, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Morgante","sequence":"additional","affiliation":[{"name":"Department of Biomedicine and Prevention, Genetics Section, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4771-6981","authenticated-orcid":false,"given":"Carlo","family":"Perricone","sequence":"additional","affiliation":[{"name":"Rheumatology, Department of Medicine and Surgery, University of Perugia, Piazzale Giorgio Menghini, 1, 06129 Perugia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fulvia","family":"Ceccarelli","sequence":"additional","affiliation":[{"name":"Lupus Clinic, Rheumatology, Department of Internal Medicine, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabrizio","family":"Conti","sequence":"additional","affiliation":[{"name":"Lupus Clinic, Rheumatology, Department of Internal Medicine, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7781-602X","authenticated-orcid":false,"given":"Giuseppe","family":"Novelli","sequence":"additional","affiliation":[{"name":"Department of Biomedicine and Prevention, Genetics Section, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3995-7032","authenticated-orcid":false,"given":"Cinzia","family":"Ciccacci","sequence":"additional","affiliation":[{"name":"UniCamillus, Saint Camillus International University of Health Sciences, 00131 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paola","family":"Borgiani","sequence":"additional","affiliation":[{"name":"Department of Biomedicine and Prevention, Genetics Section, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,8]]},"reference":[{"key":"ref_1","first-page":"e30330","article-title":"An overview of systemic lupus erythematosus (SLE) pathogenesis, classification, and management","volume":"14","author":"Ameer","year":"2022","journal-title":"Cureus"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/s41392-025-02168-0","article-title":"Systemic lupus erythematosus: Updated insights on the pathogenesis, diagnosis, prevention and therapeutics","volume":"10","author":"Dai","year":"2025","journal-title":"Signal Transduct. 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