Prioritizing endocrine-disrupting chemicals targeting systemic lupus erythematosus genes via Mendelian randomization and colocalization analyses

BACKGROUND: Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease, with both genetic and environmental influences contributing to its development. Among environmental factors, endocrine-disrupting chemicals (EDCs), present in plastics, pesticides, and personal care products, have been implicated in immune disruption. This study investigated the interactions between EDCs and SLE-associated genes to elucidate their role in SLE susceptibility. METHODS: We employed Mendelian randomization (MR) and colocalization analyses to explore genetic predispositions and environmental interactions in SLE. Cis-expression quantitative trait loci (cis-eQTL) data were obtained from the eQTLGen Consortium, and genome-wide association study (GWAS) data for SLE were acquired from the IEU Open GWAS database. MR analysis was performed to establish causal links between gene expression and SLE, and colocalization analysis was used to validate these associations. RESULTS: Our analysis identified 18 genes causally associated with SLE. Among them, five genes (CDCA7, HOXA1, LRRC37A4P, HOXA5, and DND1P1) showed strong evidence of colocalization with SLE. Further, 28 EDCs, including bisphenol A, bisphenol S, and endosulfan, were found to interact with these key genes, potentially influencing immune function and exacerbating the genetic susceptibility to SLE. CONCLUSIONS: This study highlights the complex interactions between EDCs and genetic predisposition in SLE. The findings provide valuable insights into how environmental exposures, particularly EDCs, may contribute to the development and progression of autoimmune diseases like SLE. These results suggest potential targets for future therapeutic interventions and underscore the need for further research on gene-environment interactions in SLE.