Per- and Polyfluoroalkyl Substances, Hepatic Lipid Metabolism Genes, and Hepatocellular Carcinoma: Evidence of Gene–Environment Interactions in a Multiethnic Cohort

Per- and polyfluoroalkyl substances (PFAS), synthetic pollutants that impact hepatic lipid metabolism, may increase the risk of hepatocellular carcinoma (HCC). We examined associations of prediagnostic blood PFAS levels with HCC risk and examined whether genetic susceptibility to increased hepatic lipid accumulation modified these associations. We analyzed 223 incident HCC cases and 223 matched controls from the Multiethnic Cohort. Concentrations of 12 PFAS were measured in prediagnostic plasma samples. Conditional logistic regression, adjusting for covariates, assessed PFAS–HCC associations. Effect modification was evaluated using a dichotomized polygenic risk score (PRS) for metabolic dysfunction-associated steatotic liver disease (MASLD). Each 2-fold increase in PFHpA and PFNA, respectively, was associated with 1.35 (95% CI: 1.02–1.78; p = 0.035) and 1.31 (1.00–1.72; p = 0.047) times higher HCC odds, respectively; both also exhibited significant dose–response relationships. The association between PFHpA and HCC was stronger in individuals with a high MASLD PRS. Each 2-fold increase in PFHpA was associated with a 1.47 (95% CI: 1.06–2.04; p = 0.021) times higher odds of HCC in individuals with high MASLD genetic risk, but it was not associated with HCC among those with low MASLD genetic risk (odds ratio: 0.98, 95% CI: 0.68–1.42). Although the multiplicative interaction with continuous PFAS did not reach statistical significance (p = 0.088), analyses with categorical PFHpA exposure provided evidence of a positive additive interaction. Prediagnostic concentrations of both short- and long-chain PFAS species were associated with increased HCC risk. Findings for PFHpA suggest that genetic susceptibility to hepatic lipid accumulation may modify PFAS-associated HCC risk, supporting a potential link between environmental exposures, hepatic lipid metabolism, and genetic susceptibility to HCC.