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Objectives Growing evidence supports the contribution of chemical exposures to the SLE development. 1 We aimed to classify SLE-associated loci based on nearby genes connections with chemicals, annotated by known methylation or expression changes. We performed functional enrichment analysis, constructed polygenic risk scores (PRSs) and analyzed clinical associations.Methods A total of 155 GWAS-significant SLE loci were selected. Comparative Toxicogenomics Database (CTD 2) was scanned for gene-based chemical exposure connections. The top 1/3 of the genes with the highest connection number were included in total list (TOT). Same was done for endocrine-disrupting chemicals (EDCs).3 Scandinavian patients with SLE (n=1419), fulfilling >=4 ACR-97 criteria, were genotyped by Illumina GSA. Clinical data was collected from charts. PRSs were developed for TOT and EDC loci. Associations were assessed by logistic regression adjusting for sex and age. Functional enrichment was carried out.4 Results 19 genes were unique to the TOT-PRS (e.g., IL7R and STAT4), 17 - specific to the EDC-PRS (e.g., ATXN2 and TYK2) and 26 - common to both scores (e.g., CD40 and TNFAIP3). We revealed enrichment of Toll-like receptor signaling in both groups (p=1.0e-4) and B-cell receptor signaling (p=1.6e-3) in TOT-PRS only. Both scores showed enrichment for pediatric autoimmune loci (TOT: p_adj 3.8e-9 vs EDC: p_adj 2.1e-13), and only EDC for psoriasis (p_adj 5.4e-5). Scores were associated with higher risk of malar rash (OR 1.6, p=4.4e-8, TOT-PRS; OR 1.6, p=6.9e-8, EDC-PRS) and serositis (OR 1.5, p=7.8e-7, TOT-PRS; OR 1.5, p=5.1e-7, EDC-PRS). No association was observed for discoid rash or arthritis (both p >0.05). Further, significant associations included leukopenia/lymphopenia (OR 1.3, p=2.4e-4, TOT-PRS; OR 1.7, p=2.8e-5, EDC-PRS).Conclusions We demonstrated that classification of SLE loci based on gene-chemical connections shows importance of environmental toxins exposures for SLE risk. Association between specific risk genes and chemical compounds suggests that these genes may be candidates for detecting the role of environmental exposures for SLE risk. Leveraging public functional gene-based information can also help to reveal exposome-associated mechanisms behind SLE clinical heterogeneity.References Kosarek et al. 2024, doi:10.1007/s40572-024-00444-9. Davis et al. 2024, doi:10.1093/nar/gkae883. Liu et al. 2022, doi:10.1016/j.ecoenv.2022.113382. Han et al. 2017, doi:10.1093/nar/gkx1013.