Per- and polyfluoroalkyl substances and kidney disease: Genetic associations and computational prioritization of candidate toxicogenomic pathways

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants with bioaccumulation potential, but their associations with kidney diseases remain incompletely understood. This study integrated Mendelian randomization and computational toxicology to examine associations between genetically predicted circulating PFAS levels and kidney disease outcomes and to prioritize candidate toxicogenomic pathway themes. Genetically predicted higher PFOA levels were inversely associated with IgA nephropathy (OR = 0.21, P = 0.004), but positively associated with hypertensive nephropathy (OR = 1.20, P < 0.001) and calculus of kidney (OR = 1.24, P = 0.016). Genetically predicted higher PFOS levels were inversely associated with IgA nephropathy (OR = 0.27, P = 0.046) and urinary tract infection (OR = 0.94, P = 0.003). A primary association was also observed between PFOA and membranous nephropathy (OR = 1.56, P = 0.028), but this association was not retained after targeted SNP-exclusion analyses and was therefore not interpreted as a robust or established causal association. Computational toxicology analyses prioritized database-derived candidate targets and pathway themes related to immune response, inflammation, oxidative stress, and apoptosis. Network-prioritized candidate nodes included CTNNB1, TP53, and EGFR in the PFOA-calculus of kidney network, IGF1 in the PFOA-hypertensive nephropathy network, and CCL2, TLR4, MMP9, and IFNG in the PFOA/PFOS-IgA nephropathy networks. In contrast, IL1B, TNF, and IL6 were observed as shared inflammatory nodes across multiple nephropathy-related networks. These candidates should be interpreted as database-derived and network-prioritized targets rather than experimentally validated causal mediators of kidney disease. Overall, this study provides a hypothesis-generating framework for exploring associations among genetically predicted PFAS-related traits, kidney disease outcomes, and candidate toxicogenomic pathway themes that require experimental validation.