An ETS2 Enhancer Variant May Modulate Gene Expression and Contribute to Defining a Genetic Risk Profile for SLE Susceptibility

<b>Background/Objectives</b>: 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 <i>ETS2</i> proto-oncogene, has been implicated in immune regulation, though its contribution to SLE is unclear. <b>Methods</b>: 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. <i>ETS2</i> mRNA expression was quantified by RT-qPCR in PBMCs from 60 individuals, and in silico analyses assessed the variant's functional context. <b>Results</b>: The rs2836882 risk allele was significantly associated with SLE (OR = 1.54, <i>p</i> = 0.02). Patients showed a markedly higher wGRS than controls (<i>p</i> < 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 <i>ETS2</i>. Expression analysis demonstrated that carriers of the risk allele exhibited significantly increased <i>ETS2</i> expression compared to non-carriers (<i>p</i> = 0.002) in both groups. <b>Conclusions</b>: In conclusion, rs2836882 is a functional regulatory variant that enhances <i>ETS2</i> 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.