Per- and polyfluoroalkyl substances and kidney disease: Genetic associations and computational prioritization of candidate toxicogenomic pathways
5 affiliations
- 1Department of Urology, The Second Xiangya Hospital at Central South University, Changsha, Hunan, China
- 2Department of Nephrology, The Second Xiangya Hospital at Central South University, Changsha, Hunan, China
- 3Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- 4The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan, China
- 5Department of General Surgery, The Second Xiangya Hospital at Central South University, Changsha, Hunan, China
Abstract
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. Author summary: Per- and polyfluoroalkyl substances (PFAS) are a group of persistent environmental chemicals widely detected in water, food, consumer products, and human blood. Because the kidneys are involved in filtration, tubular handling, and chemical elimination, they may be particularly relevant to long-term PFAS-related biological effects. However, it remains challenging to determine how circulating PFAS-related traits are associated with specific kidney disease outcomes and which molecular pathway themes warrant further study. In this study, we combined genetic epidemiology with computational toxicology to investigate associations between genetically predicted circulating PFAS-related traits and several kidney disease outcomes. Our genetic analyses suggested that PFOA and PFOS were associated with different kidney diseases in distinct directions. We then used computational approaches to prioritize database-derived candidate protein targets and pathway themes related to immune regulation, inflammation, oxidative stress, and apoptosis. By integrating population-level genetic evidence with computational target prioritization, this study provides a hypothesis-generating framework for future experimental studies on PFAS-related kidney health.
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BibTeX
@article{zeng2026polyfluoroalkyl,
title = {{Per- and polyfluoroalkyl substances and kidney disease: Genetic associations and computational prioritization of candidate toxicogenomic pathways}},
author = {Dianjie Zeng and Yuxi Wang and Yinhuai Wang and Guoqiang Li and Wenpeng Wang and Zhongkun Zuo},
journal = {PLOS Computational Biology},
year = {2026},
month = sep,
doi = {10.1371/journal.pcbi.1014665},
url = {https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014665},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Per- and polyfluoroalkyl substances and kidney disease: Genetic associations and computational prioritization of candidate toxicogenomic pathways
AU - Dianjie Zeng
AU - Yuxi Wang
AU - Yinhuai Wang
AU - Guoqiang Li
AU - Wenpeng Wang
AU - Zhongkun Zuo
PY - 2026
DA - 2026/09/17
JO - PLOS Computational Biology
DO - 10.1371/journal.pcbi.1014665
UR - https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014665
AB - 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. Author summary: Per- and polyfluoroalkyl substances (PFAS) are a group of persistent environmental chemicals widely detected in water, food, consumer products, and human blood. Because the kidneys are involved in filtration, tubular handling, and chemical elimination, they may be particularly relevant to long-term PFAS-related biological effects. However, it remains challenging to determine how circulating PFAS-related traits are associated with specific kidney disease outcomes and which molecular pathway themes warrant further study. In this study, we combined genetic epidemiology with computational toxicology to investigate associations between genetically predicted circulating PFAS-related traits and several kidney disease outcomes. Our genetic analyses suggested that PFOA and PFOS were associated with different kidney diseases in distinct directions. We then used computational approaches to prioritize database-derived candidate protein targets and pathway themes related to immune regulation, inflammation, oxidative stress, and apoptosis. By integrating population-level genetic evidence with computational target prioritization, this study provides a hypothesis-generating framework for future experimental studies on PFAS-related kidney health.
SN - 1553-7358
ER -