B CELL POLYGENIC RISK SCORES ASSOCIATED WITH ANTI-DSDNA ANTIBODIES AND NEPHRITIS IN SYSTEMIC LUPUS ERYTHEMATOSUS

A. Hedenstedt, S. Reid, A. Sayadi, M. L. Eloranta, E. Skoglund, K. Bolin, M. Frodlund, K. Lerang, A. Jonsen, S. Rantapää Dahlqvist, A. Bengtsson, A. Rudin, Ø. Molberg, C. Sjowall, J. Sandling, D. LeonardUppsala University, Department of Medical Sciences, Uppsala, Sweden Linköping University, Department of Biomedical and Clinical Sciences, Linköping, Sweden Oslo University Hospital, Department of Rheumatology, Oslo, Norway Lund University, Department of Clinical Sciences, Lund, Sweden Umeå University, Department of Public Health and Clinical Medicine/Rheumatology, Umeå, Sweden Sahlgrenska Academy, University of Gothenburg, Dept of Rheumatology and Inflammation Research, Gothenburg, Sweden  Background Lupus nephritis (LN) is one of the main clinical challenges in systemic lupus erythematosus (SLE) and a cause of significant morbidity and mortality. Genetic contribution to SLE pathogenesis is important, and genetic profiling through polygenic risk scores has been shown useful to stratify SLE patients according to dominating molecular disease mechanism. This has not, however, been investigated for specific disease manifestations. Objectives In this work, we aimed to investigate associations between B cell polygenic risk scores (PRSs) and disease manifestations in SLE. Methods Female patients with SLE (n = 1248) and healthy control individuals (n = 519) were genotyped using Illumina’s Global Screening Array. Two PRSs were calculated, one including 20 GWS risk loci for SLE in genes assigned to B-cell related pathways according to the KEGG, GO and Reactome databases, and one including a subset of 12 of these genes limited to B-cell activation pathways. PRSs were defined as high in the highest quartile and low in quartile 1-3, and groups were compared by logistic regression (SPSS, version 28.0.1.0). HLA variants HLA-DRB1*03:01 and HLA-DRB1*15:01 were assessed in patients using tag SNPs. A p-value < 0.05 was considered significant. Results SLE was more prevalent in individuals with high compared with a low SLE B cell PRS (OR 1.84 (1.42-2.38), p=4.0×10) and mean PRS was higher in cases than controls, 2.92 (2.88-2.96) for cases and 2.68 (2.63-2.74) for controls, p = 4.1 × 10). Immunologic disorder (ACR -82) and dsDNA antibodies were more prevalent among patients with a high compared with a low SLE B cell PRS (OR 1.44 (1.08-1.93), p=1.4×10, and OR 1.47 (1.07-2.01), p=1.8×10, for immunologic disorder and dsDNA antibodies, respectively). Also, effect sizes were augmented in patients with HLA risk serotypes HLA-DRB1*03:01 and HLA-DRB1*15:01, with the highest prevalence of dsDNA antibodies (87 %) demonstrated in patients with HLA-DRB1*03/15 +/+ combined with a high SLE B cell PRS (OR 1.64 (1.06-2.54), p = 0.028, for high vs low PRS), Figure 1. Anti-dsDNA antibodies were associated with a higher prevalence of class III or IV nephritis (OR 4.66 (2.78-7.80), p=5.2×10 and the prevalence of nephritis according to the ACR-82 criteria was higher in patients with a high compared to patients with a low B cell activation PRS (OR 1.32 (1.00-1.74), p = 0.048). Numerically, a higher prevalence of nephritis (ACR -82) was observed for patients with a high compared with a low SLE B cell PRS, but the difference was not statistically significant (OR 1.20 (0.91-1.59), p = 0.19). Conclusion High genetic burden related to B cell function is associated with dsDNA antibody development and LN. Assessing B cell PRSs may be important in order to determine immunologic pathways influencing SLE and to predict clinical phenotype. References Sandling, J.K. et al. Molecular pathways in patients with systemic lupus erythematosus revealed by gene-centred DNA sequencing. Ann Rheum Dis 80, 109-117 (2021). Reid, S. et al. High genetic risk score is associated with early disease onset, damage accrual and decreased survival in systemic lupus erythematosus. Ann Rheum Dis 79, 363-369 (2020). Image/graph:Figure 1. Associations with SLE B cell PRS, immunologic disorder (ACR-82) and anti-dsDNA antibodies in HLA subgroups. Female patients with SLE were stratified into three groups according to HLA-type (positive for HLA-DRB1*03:01 or HLA-DRB1*15:01 (DRB1*03/15 +/- or -/+), positive for both (DRB1*03/15 +/+) or negative for both (DRB1*03/15 -/-) risk variants). Each group was then divided into two groups based on the patients’ SLE B cell PRSs (highest quartile or quartile 1-3). Prevalence of immunologic disorder according to the ACR -82 criteria (A) and prevalence of dsDNA antibodies (B) was then calculated for all 6 groups. ACR, American College of Rheumatology; dsDNA, double-stranded DNA; HLA, human leukocyte antigen; SLE, systemic lupus erythematosus; SNP, single nucleotide polymorphism; PRS, polygenic risk score. Acknowledgements: NIL. Disclosure of Interests None Declared. Keywords: Autoantibodies, Genetics/Epigenetics, Systemic lupus erythematosus DOI: 10.1136/annrheumdis-2023-eular.6203Citation: , volume 82, supplement 1, year 2023, page 68Session: Genetics and EpiGenetics of RMDs (Oral Presentations)