Associations between per- and polyfluoroalkyl substances and metabolic dysfunction-associated steatotic liver disease in adolescents and young adults: modifying roles of age, lifestyle factors, and PNPLA3 genotype.

Studies in youth on per- and polyfluoroalkyl substances (PFAS) exposure and metabolic dysfunction-associated steatotic liver disease (MASLD) are limited. The study aimed to evaluate associations between PFAS and MASLD risk and the modifying role of age, lifestyle factors, and genetic risk. We analyzed data from two independent cohorts: the Study of Latino Adolescents at Risk of Type 2 Diabetes (SOLAR) following adolescents aged 8-13 years over 6 years (n = 162; recruited between 2001 and 2012); and the Metabolic and Asthma Incidence Research (Meta-AIR) study of young adults aged 17-23 years (n = 122; recruited between 2014 and 2018). Eight PFAS were measured in plasma using liquid chromatography-high-resolution mass spectrometry. MASLD was defined as hepatic fat fraction >5.5 % on magnetic resonance imaging plus ≥1 cardiometabolic risk factor (high BMI, fasting glucose, blood pressure, triglycerides, and low high-density lipoprotein). Firth's penalized logistic regression models estimated associations between PFAS and MASLD. We evaluated the interaction between each PFAS and age, lifestyle factors (cigarette smoking, alcohol drinking, physical activity, sleep duration, and diet in adult cohort), and PNPLA3 genotype, a key liver fat-regulating gene. Among adolescents, each doubling in plasma PFOA was associated with higher odds of MASLD (OR = 2.69; 95 % CI: 1.16-6.26; p = 0.02), and the association strengthened with increasing age (PFOA × Age OR = 1.45; 95 % CI: 1.03-2.06; p = 0.04). Risk was further elevated among older adolescents and those with PNPLA3 risk allele. Among young adults, overall associations were not significant, but MASLD risk was higher among smokers with elevated PFDA, PFHpS, and PFNA levels (interaction p = 0.01, 0.02, 0.02, 0.03, respectively). Our findings support that PFAS may increase the risk of MASLD in youth, with age, genetics, and smoking modifying susceptibility.