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Objectives Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by heterogeneous clinical manifestations. Although its precise pathogenesis remains incompletely understood, multiple genetic risk loci have been identified, particularly within genes implicated in both innate and adaptive immune pathways. Moreover, specific genetic variants and altered cytokine profiles have been associated with disease activity and distinct clinical phenotypes.Methods Using Sanger sequencing, we examined 90 patients with SLE and 81 healthy controls for the presence of selected risk variants in susceptibility genes such as BANK1, CTLA4, DNASE1, and IRF5. We also measured serum levels of interferon gamma-induced protein 10 (IP-10) and interleukin-18 (IL-18) in 124 patients and 112 controls using the ELISA method, and B-cell activating factor (BAFF) in a subset of 71 patients and 48 healthy controls.Results We identified 16 genetic variants that have previously been reported in the literature as potentially associated with autoimmune diseases and SLE. However, no statistically significant differences in their allelic frequencies were observed compared to controls. The following rare variants were detected exclusively in patients and were not observed in healthy controls: p.Glu35Asp, p.Val185Ile, and c.437-19G>A in the DNASE1 gene; c.71-53T>C in the BANK1 gene; and two rare UTR variants: c.34A>G in CTLA4 and c.36G>A in IRF5.We detected significantly higher serum levels of IP-10 and IL-18 in patients compared to healthy subjects (p-value < 0.0001). When divided into patients with active disease and those in remission, we found significant differences in IL-18 (p= 0.023). Higher serum levels of IP-10 and IL-18 were associated with increased disease activity as measured by the SLEDAI score (Systemic Lupus Erythematosus Disease Activity Index); IP-10: p < 0.001, IL-18: p = 0.07. In addition, IP-10 and IL-18 levels showed a positive correlation with each other. We also found significantly higher serum levels of BAFF in patients than in controls (p = 0.018).Conclusions Our findings suggest that certain genetic variants may contribute to SLE susceptibility. Elevated serum levels of IP-10 and IL-18 were associated with increased disease activity, highlighting their potential as biomarkers of disease severity.Acknowledgement Supported by Ministry of Health of the Czech Republic, grant nr. NW24J-10-00024.