SLE Genetic Risk Loci in the Context of Environmental Exposure: A Gene-Based Classification and Clinical Insight

Nina Oparina¹, Holme Vestin¹, Sarah Reid¹, Ahmne Sayadi¹, Maija-Leena Eloranta¹, Martina Frodlund², Karoline Lerang³, Andreas Jönsen⁴, Øyvind Molberg³, Solbritt Rantapää-Dahlqvist⁵, Anna Rudin⁶, Chrisopher Sjöwall⁷, Anders Bengtsson⁴, Lars Rönnblom¹ and Dag Leonard¹, ¹Department of Medical Sciences, Uppsala University, Uppsala, Sweden, ²Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection/Rheumatology, Linköping University, Linköping, Linkoping, Sweden, ³Department of Rheumatology, Oslo University Hospital, Oslo, Norway, ⁴Department of Clinical Sciences, Lund University, Lund, Sweden, ⁵Department of Public Health and Clinical Medicine/Rheumatology, Umeå University, Umeå, Sweden, ⁶Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy of University of Gothenburg, Gothenburg, Sweden, ⁷Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection/Rheumatology, Linköping University, Linköping, Sweden

Meeting: ACR Convergence 2025

Keywords: Environmental factors, genetics, Systemic lupus erythematosus (SLE)

Session Information

Date: Tuesday, October 28, 2025

Title: (2377–2436) Systemic Lupus Erythematosus – Diagnosis, Manifestations, & Outcomes Poster III

Session Type: Poster Session C

Session Time: 10:30AM-12:30PM

Background/Purpose: Growing evidence supports the role of chemical exposures as contributors to the development of Systemic lupus erythematosus (SLE)1. Several of the gene variants associated with SLE appear to be responsive to various environmental substances. We aimed to classify SLE-associated loci based on gene-chemical connection and to reveal potential exposure-based differences. We performed functional enrichment analysis, constructed polygenic risk scores (PRSs) and analyzed clinical phenotype associations.

Methods: A total of 155 genome-wide association study (GWAS) significant (p=5e-8) SLE single nucleotide variants (SNVs) were selected (based on European ancestry). Comparative Toxicogenomics Database (CTD2) was scanned for chemical exposure connection with these genes. A gene-chemical interaction analysis was performed. The top 1/3 of the genes with the highest number of gene–chemical connections were selected and denoted as total (TOT). Separately, we analyzed the number of interactions for endocrine-disrupting chemicals (EDCs)3.Scandinavian patients with SLE (n=1419), fulfilling ≥4 ACR-97 criteria, were genotyped by Illumina Global Screening Array. Clinical data was collected from charts. SLE environmental exposure weighted polygenic risk scores (PRSs) were developed including the TOT and EDC risk loci. Regression analysis compared the top quartile to the remaining individuals adjusting for sex and age. Functional enrichment was carried out using KEGG, TRRUS4 and Reactome databases.

Results: In total, 19 of top genes identified in the CTD database were included exclusively in the TOT-PRS (including IL7R and STAT4), and 17 were specific to the EDC-PRS (including ATXN2 and TYK2). The highest number of interactions was observed for IL10 (n=3169).Pathway analysis showed enrichment of Toll-like receptor signaling in both groups (p=1.0e-4), while B-cell receptor signaling (p=1.6e-3) was enriched in TOT-PRS only. Both 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), nephritis (OR 1.7, p=8.1e-14, TOT-PRS; OR 1.6, p=9.2e-14, 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, the PRSs showed association with thrombocytopenia (OR 1.1, p=0.02, TOT-PRS; OR 1.5, p=5.5e-3, EDC-PRS) and leukopenia/lymphopenia (OR 1.3, p=2.4e-4, TOT-PRS; OR 1.7, p=2.8e-5, EDC-PRS).

Conclusion: We demonstrated that classification of SLE loci based on gene-chemical connections can identify potential connections between selected risk genes and chemical compounds. A strong association between specific risk genes and a large number of chemical compounds suggests that these genes may be important targets when investigating the role of environmental exposures to risk for disease. Leveraging public functional gene-based information can also help to reveal exposome-associated mechanisms behind SLE clinical heterogeneity. References:1. Kosarek et al. 2024, doi:10.1007/s40572-024-00444-9.2. Davis et al. 2024, doi:10.1093/nar/gkae883.3. Liu et al. 2022, doi:10.1016/j.ecoenv.2022.113382.4. Han et al. 2017, doi:10.1093/nar/gkx1013.

Disclosures: N. Oparina: None; H. Vestin: None; S. Reid: None; A. Sayadi: None; M. Eloranta: None; M. Frodlund: None; K. Lerang: None; A. Jönsen: None; Ø. Molberg: None; S. Rantapää-Dahlqvist: None; A. Rudin: None; C. Sjöwall: Bristol-Myers Squibb(BMS), 3; A. Bengtsson: None; L. Rönnblom: AstraZeneca, 6, Biogen, 2; D. Leonard: None.

To cite this abstract in AMA style:

Oparina N, Vestin H, Reid S, Sayadi A, Eloranta M, Frodlund M, Lerang K, Jönsen A, Molberg Ø, Rantapää-Dahlqvist S, Rudin A, Sjöwall C, Bengtsson A, Rönnblom L, Leonard D. SLE Genetic Risk Loci in the Context of Environmental Exposure: A Gene-Based Classification and Clinical Insight [abstract]. Arthritis Rheumatol. 2025; 77 (suppl 9). https://acrabstracts.org/abstract/sle-genetic-risk-loci-in-the-context-of-environmental-exposure-a-gene-based-classification-and-clinical-insight/. Accessed .

« Back to ACR Convergence 2025

ACR Meeting Abstracts - https://acrabstracts.org/abstract/sle-genetic-risk-loci-in-the-context-of-environmental-exposure-a-gene-based-classification-and-clinical-insight/