Patients with systemic lupus erythematosus (SLE) have an increased bisphenol A methylation score linked to SLE risk genes and selected clinical subphenotypes.

Objectives: 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.

Methods: 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 BPA_All score including 19 CpGs and a BPA_SLE 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.

Results: Patients with SLE had significantly higher BPA_SLE 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 BPA_All 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 BPA_SLE 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.

Conclusions: 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.