Sex-Specific Associations Between Per- and Polyfluoroalkyl Substances and the Risk of Type 2 Diabetes: The Role of Genetic Susceptibility and Lipid Metabolism

Abstract

To elucidate the sex-specific associations of per- and polyfluoroalkyl substances (PFASs) on type 2 diabetes (T2D) risk and to explore whether genetic susceptibility and baseline lipid profiles may help explain these associations. A nested case-control study including 985 matched case-control pairs from the Dongfeng-Tongji Cohort was conducted. Serum PFAS concentrations, T2D-related pathway polygenic risk scores (PRSs), blood lipid profiles, and plasma lipidomes were integrated. Conditional logistic regression, weighted quantile sum (WQS) regression, mediation analysis, and gene-environment interaction analysis were used to explore the associations and mechanisms. Sex-specific associations were observed between PFAS exposure and incident T2D, with PFOA and PFNA being associated with higher T2D risk in females. Liver-lipid pathway PRS strengthened these sex-specific associations. PFAS exposure was associated with triglyceride-related lipid profiles in females. Exploratory analyses suggested that the lipid score statistically accounted for part of the selected PFAS-T2D associations. CYP19A1-rs2414098 modified the association in females, with 50% mediation by the lipid score in the CC genotype (higher estrone). Baseline lipid profiles may partly account for the observed sex-specific associations between PFAS exposure and incident T2D. The observed effect modification by CYP19A1 rs2414098 suggests that hormonal pathways may contribute to the sex-specific associations, although this hypothesis requires confirmation in studies with direct hormone measurements and experimental validation.