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Objectives Patients with systemic lupus erythematosus (SLE) who carry a high genetic burden often experience more severe disease. To understand the molecular consequences of polygenic risk, we analyzed single-cell gene expression profiles in SLE patients stratified by genetic risk.Methods Single-cell RNA sequencing (scRNA-Seq) was performed on peripheral blood mononuclear cells (PBMC) from 16 female SLE patients, stratified by a weighted polygenic risk score (PRS)1, and 6 healthy controls (HCs). All patients were in low disease activity (LLDAS) and treated with antimalarials only, and were not receiving prednisolone. We assessed differential gene expression, interferon (IFN) signatures, transcription factor (TF) activity, and pathway enrichment across the High-PRS, Low-PRS, and HC groups.Results The average PRS was higher in the High-PRS (9.9 ± 0.6) compared with the Low-PRS group (7.3 ± 0.6). Prescribed hydroxychloroquine doses were comparable between groups (High-PRS: 1,733 mg/week; Low-PRS: 1,833 mg/week; p=0.71), as were serum concentrations (High-PRS: 1461 ± 683 ng/ml; Low-PRS 999 ± 497 ng/ml; p=0.22).Following quality control, 184,966 single cells were retained for analysis, averaging 9,636 cells per individual and 2,724 genes detected per cell. Differential gene expression analysis revealed a higher number of differentially expressed genes (DEGs, adjusted p<0.05, log2FC>0.25) in High-PRS vs. HCs (n=1,760 ), compared with Low-PRS vs. HCs (n=694).High-PRS patients exhibited significantly elevated IFN scores relative to HCs (p<0.001), while no significant difference was observed between Low-PRS patients and HCs, figure 1. This trend was consistent across multiple immune cell types, including T cells, NK cells, and monocytes.Increased expression of key IFN-stimulated genes was noted in High-PRS patients, including ISG15 and USP18 in plasmacytoid dendritic cells (pDCs), and IFI27 and RSAD2 in monocytes. IFN-related pathways were enriched in pDCs and monocytes in High-PRS patients, and only in monocytes in Low-PRS patients. Transcription factor analysis identified IRF7 and BATF3 as key candidate regulators in both cell types among High-PRS patients.Abstract PO:06:175 Figure 1Cell type specific IFN score in SLE patients stratified by polygenic risk score. Distribution of interferon (IFN) scores per sample across all annotated cell types. (A) Comparison of High-PRS versus HCs and (B) Low-PRS versus HCs. The scores were calculated per cell and averaged per sample. (C, D) IFN responsescores stratified by cell types for (C) High-PRS vs HCs and (D) Low-PRS vs HCs.Statistical significance was evaluated using the Mann-Whitney U test.Conclusions High polygenic risk in SLE is associated with persistent activation of IFN signalling pathways, indicating that antimalarial treatment alone may be insufficient to fully suppress IFN activity, even during clinical remission.Reference Reid S. et al. Annals of the Rheumatic Diseases. 2019