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Introduction – Paraoxonase 1 (PON1) is a liver-derived HDL-associated enzyme with key antioxidant functions implicated in cardiometabolic disease. Genetic variation in PON1 strongly influences enzyme activity; however, whether specific genetic configurations contribute to dysglycemia and metabolic liver risk beyond enzymatic activity remains unclear. Methods – We analyzed 922 individuals from the PREVADIAB2 cohort to investigate the relationship between PON1 genetic variation, serum paraoxonase (PONase) activity, and dysmetabolic phenotypes. Genetic determinants of PONase activity were identified using genome-wide analysis. Independent variants were combined into haplotypes, and their associations with dysglycemia and metabolic liver risk (Fibrotic NASH Index, FNI) were assessed in individuals aged >55 years. Results – Two independent PON1 variants—rs2057681 (in strong linkage disequilibrium with Q192R) and the promoter variant rs854572—were identified as major determinants of PONase activity. Haplotype analysis revealed that promoter–transcribed region combinations exert graded effects on enzyme activity. Importantly, these genetic configurations were differentially associated with dysglycemia and metabolic liver risk in a genotype-dependent manner. In carriers of the rs2057681 G allele, the C–A haplotype was associated with lower risk of dysglycemia and elevated FNI, whereas in rs2057681 AA homozygotes the same haplotype showed an opposite association with metabolic liver risk. Notably, despite strong genetic effects on PONase activity, enzyme activity itself was not directly associated with dysmetabolic phenotypes. Discussion – PON1 genetic architecture, defined by promoter– transcribed region interactions, is associated with dysglycemia and metabolic liver risk in a genotype-dependent manner beyond steady-state enzyme activity. These findings provide insight into the genetic regulation of metabolic risk and may help explain inconsistent associations of PON1 variants in cardiometabolic disease.