Genetic variations interact with polybrominated diphenyl ether exposure to alter lipid homeostasis

作者：Naifan Hu, Bin Li, Yifu Lu, Qi Jiang, Ying Zhu, Zheng Li, Yingli Qu, Tian Qiu, Donghui Zhang, Zhuo Wang, Yunfei Ma, Huibin Jin, Peijie Sun, Haocan Song, Yunhao Zhao, Yifan Zhao (659636), MING SEN ZHANG, Feng Zhao, Saisai Ji, Bifeng Yuan, Ying Zhu, Yuebin Lv, Jianbo Tian, Xiaoping Miao, Xiaoming Shi · 发表于：Nature Communications · 年份：2026 · DOI：10.1038/s41467-026-70222-8 · 被引用次数：1 · 研究领域：Toxic Organic Pollutants Impact、Effects and risks of endocrine disrupting chemicals、Carcinogens and Genotoxicity Assessment

Polybrominated diphenyl ethers (PBDEs) are implicated in dyslipidemia, but the molecular basis of individual susceptibility remains elusive. Here we report an analysis based on the China National Human Biomonitoring cohort, where we integrate exposome, genomic, and metabolomic data to identify 3,571 genetic variants that interact with PBDE exposure to influence dyslipidemia risk. Metabolomic analysis highlights glycine and glycerophosphate as key mediators. A polygenic risk score derived from these PBDE-interactive variants significantly enhances dyslipidemia prediction in highly exposed individuals. Among these, rs9869609 emerges as a candidate causal variant, showing the strongest association with hypercholesterolemia risk (β = 1.18, FDR = 0.0078). Further functional validation using single-base CRISPR/Cas9 editing reveals that the rs9869609-G allele downregulates SLC6A20 expression by strengthening BHLHE40 binding, which further impairs glycine transport and promotes cholesterol accumulation, particularly under 2,2′,4,4′-Tetrabromodiphenyl ether exposure. Collectively, our study elucidates a gene-environment interaction mechanism through which genetic variants modulate lipid metabolism in response to PBDE exposure. Polybrominated diphenyl ethers (PBDEs) are linked to dyslipidemia, but why individuals respond differently is unclear. Here, the authors use a national biomonitoring cohort to reveal how specific genetic variants interact with PBDE exposure to increase risk, ide...