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Accumulating evidence supports the implication of long non-coding RNAs (lncRNAs) in autoimmune diseases, including systemic lupus erythematosus (SLE). LncRNA variants could impact the development and/or outcome of the disease with variable diagnostic/prognostic utility in the clinic. We aimed to explore the contribution of HOTAIR (rs10783618), LINC-ROR (rs1942347), and MALAT1 (rs3200401) variants to SLE susceptibility and/or severity in 163 SLE patients and age-/sex-matched controls using real-time TaqMan allelic discrimination PCR. HOTAIR rs10783618*C/C was associated with a 77% increased risk of SLE (OR = 1.77, 95%CI = 1.09–2.87, p = 0.020) under the recessive model. Similarly, MALAT1 rs3200401*T/T carriers were three times more likely to develop SLE (OR = 2.89, 95%CI = 1.42–5.90) under the recessive model. While the rs3200401*T/C genotype was associated with a 49–57% decreased risk of SLE under codominant (OR = 0.51, 95%CI = 0.31–0.82, p < 0.001) and over-dominant (OR = 0.43, 95%CI = 0.27–0.68, p < 0.001) models. LINC-ROR rs1942347*A/A patients were more likely to have a positive family history of SLE. At the same time, HOTAIR rs10783618*C/C was associated with a higher frequency of arthritis (p = 0.001) and the presence of oral ulcers (p = 0.002), while patients carrying rs10783618*T/T genotype were more likely to develop hair loss (p < 0.001), weight loss (p = 0.001), and neurological symptoms (p = 0.003). In conclusion, the studied lncRNAs, HOTAIR, and MALAT1 gene polymorphisms confer susceptibility for SLE, providing a potential theoretical basis for their clinical translation in SLE disease. [ABSTRACT FROM AUTHOR]