Background/Purpose: The pathogenesis of SLE involves genetic, environmental and epigenetic factors (1). Increased levels of Bisphenol A (BPA) have been observed in the urine of patients with SLE (2). Since altered immune responses and DNA methylation changes have been observed following BPA treatment in vitro (3, 4), we aimed to investigate if a BPA methylation score associate with SLE and whether it can be linked to SLE risk genes and gene expression changes in immune signalling pathways.

Methods: Potential BPA sensitivity of 198 genes for SLE genetic loci (GWAS catalogue, p≤5×10-8, reported in ≥2 studies) was tested using gene-chemical interactions data from the Comparative Toxicogenomics Database (CTD). Swedish patients with SLE fulfilling ≥ 4 ACR-82 criteria (n=548) and healthy controls (n=587) from a discovery and replication cohort were included. DNA methylation levels were investigated by the Illumina HM450k array. CpG sites reported as differentially methylated in blood in ≥2 of 7 BPA exposure studies and verified in DepMap (n=19 loci) were selected for calculation of a BPAAll score based on all 19 CpG sites and a BPASLE score based on three of the sites collocated with GWAS SLE risk loci. Interferon (IFN) regulation status was determined using the database Interferome. Clinical data were collected from patient charts. BPA treatment effects were checked using GEO2R-recalculated publicly available gene expression data from four BPA-treated cell lines; Ishikawa, HepG2, Y79 and MCF7. Functional enrichment was estimated using PANTHER pathways.

Results: For 152 (77%) of the 198 SLE risk genes, BPA was among the top ten gene-interacting chemicals in CTD. BPA was the top interacting compound for 50 (25%) of the genes. Patients with SLE had significantly higher BPASLE score compared with controls in the discovery (OR 1.34, p=4.6×10-13), replication (OR 1.28, p=1.1×10-5), and meta-analysis (OR 1.32, p=3.3×10-17). Higher BPAAll score associated with SLE in the discovery (OR 1.05, p=2.3×10-3) but not in the replication cohort with a significant difference in the meta-analysis (OR 1.05, p=7.0×10-4). In the combined cohort, both scores associated with prednisolone treatment (p < 0.001) and the BPASLE score associated with serositis (p=0.019) and anti-RNP antibodies (p=0.027). BPA-induced gene expression changes common for ≥2 of four cell lines showed enrichment of B cell activation, MAP kinase cascade and IFN-γ (type II IFN) signaling pathways. Out of the 29 genes annotated to the BPA-sensitive sites, 20 (69%) were reported as type II IFN-regulated in Interferome and 10 (34%) were reported as differentially expressed in at least one of the four cell lines, of which MAP3K9 exhibited the most significant change (logFC 1.17, p=2.1x10-17). One of the genes annotated to a an SLE-collocated BPA-sensitive CpG site, MICB, was differentially expressed.

Conclusion: This is the first study to suggest an association between BPA exposure and epigenetic changes in SLE, possibly altering expression of genes involved in immune response pathways such as IFN-γ and MAPK signalling. References1. Tsokos GC. Nat. Immunol. 20242. Wang Y, et al. Ecotoxicol. Environ. Saf. 20243. Panchanathan R, et al. Mol Cell Endocrinol. 20154. Besaratinia A. Int J Mol Sci. 2023

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/patients-with-sle-have-an-increased-bisphenol-a-methylation-score-linked-to-sle-risk-genes-and-immune-response-pathways/