Patients with systemic lupus erythematosus (SLE) have an increased bisphenol A methylation score linked to SLE risk genes and selected clinical subphenotypes.
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Vestin H, Oparina N, Eloranta ML, Frodlund M, Gunnarsson I, Sjöwall C, Svenungsson E, Rönnblom L, Imgenberg-Kreuz J, Leonard D
RMD Open 11 (3) - [2025-09-25; online 2025-09-25]
Bisphenol A (BPA), a xenoestrogen that can alter DNA methylation status, has been implicated in the pathogenesis of systemic lupus erythematosus (SLE). This study aimed to investigate whether methylation changes at BPA-sensitive 5'-C-phosphate-G-3' (CpG) sites are associated with SLE and clinical subphenotypes. A discovery cohort (n=747) and a replication cohort (n=388) including Swedish patients with SLE and healthy controls were investigated using the Illumina HM450k bead chip. BPA-sensitive CpG sites were selected if differentially methylated in ≥2 of 7 BPA exposure studies and supported by cell line data. A BPAAll score including 19 CpGs and a BPASLE score based on three CpG sites co-localised in the genome with SLE risk loci were calculated for each individual, analysed for associations with clinical data and then compared with publicly available transcriptomic data from BPA-treated cells. Patients with SLE had significantly higher BPASLE score than 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 was associated with SLE in the discovery cohort (OR 1.05, p=2.3×10-3) but not in the replication cohort (OR 1.04, p=0.12) with a significant difference in the meta-analysis (OR 1.05, p=7.0×10-4). Both scores were associated with prednisolone treatment (p<0.001), and the BPASLE score was associated with serositis and autoantibodies (p<0.05). Transcriptomic analysis of BPA-treated cells revealed enrichment in pathways such as interferon and mitogen-activated protein kinase signalling. Our findings reveal a novel association between BPA exposure and DNA methylation changes in SLE, with potential implications for the regulation of immune-related gene expression.
NGI Uppsala (SNP&SEQ Technology Platform) [Service]
National Genomics Infrastructure [Service]
PubMed 40998523
DOI 10.1136/rmdopen-2025-006021
Crossref 10.1136/rmdopen-2025-006021
pmc: PMC12481292
pii: rmdopen-2025-006021