Background & Aims Metabolic disorders such as dyslipidemia, metabolic dysfunction–associated steatotic liver disease (MASLD), and diabetes are promoted by chronic pro-inflammatory and pro-oxidative states. Paraoxonase 1 (PON1), a liver-derived HDL-associated enzyme, plays an important antioxidant role by hydrolyzing oxidized lipids and protecting against oxidative stress– induced damage. Genetic variation in PON1, particularly in promoter and coding regions, modulates enzyme expression and activity, thereby influencing susceptibility to metabolic and cardiovascular diseases. This study investigated the genetic determinants of serum paraoxonase (PONase) activity and their relationship with dysmetabolic phenotypes.

Methods A genome-wide association study was conducted in 922 Portuguese individuals from the PREVADIAB2 cohort. Genetic variants and haplotypes related to PONase activity were analyzed, and associations with dysglycemia and liver fibrosis were evaluated in individuals aged over 55 years.

Results We identified two key PON1 variants as determinants of PONase activity: rs2057681 (in strong linkage disequilibrium with the non-synonymous Q192R variant) and rs854572 (located in the promoter region). Analysis of rs854572–rs2057681 haplotypes revealed that specific combinations differentially modulate PONase activity and confer risk or protection for dysglycemia and liver fibrosis, depending on the rs2057681 genotype context. Notably, although PONase activity was strongly associated with PON1 variants, it did not directly correlate with dysmetabolic phenotypes, suggesting that genetic context and haplotype structure, rather than enzyme activity alone, shape disease susceptibility.

Conclusions These findings highlight the complex genetic architecture of PON1 and its role in metabolic disease risk, supporting the use of PON1 genetic information to uncover predisposition to dysmetabolic conditions. Our results provide insights into the interplay between PON1 genetics, enzyme function, and dysmetabolism, with implications for risk stratification in metabolic liver disease.

Lay Summary PON1 is a liver-derived gene that encodes an enzyme involved in protection against oxidative stress, a key contributor to metabolic liver disease and diabetes. In this study, we found that specific combinations of PON1 genetic variants are associated with abnormalities in blood glucose regulation and with markers of liver fibrosis. These associations were dependent on genetic configuration rather than enzyme activity alone, suggesting that PON1 genetic information may help identify individuals at higher risk of metabolic liver disease.

The authors have declared no competing interest.

this work was supported by the Fundacao para a Ciencia e a Tecnologia to MJM (PD/BD/114256/2016) and LH (2024.03785.BDANA), and the European Commission, Horizon Europe Framework Programme, PAS GRAS (Grant agreement n. 101080329).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The protocol followed the principles of the Declaration of Helsinki and received approval from the Ethics Committee of Associacao Protectora dos Diabeticos de Portugal (APDP Diabetes Portugal (900/2013)) and NOVA Medical School (CEFCM/02/2020), as well as from the Portuguese Data Protection Authority (permit no. 3228/2013).

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Yes

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Data availability statement:All data presented in this manuscript will be available upon request to collaborative academic researchers for non-profit research purposes only.

Funding statement: this work was supported by “Fundação para a Ciência e a Tecnologia” – FCT to MJM (PD/BD/114256/2016), LH (2024.03785.BDANA), and the European Commission, Horizon Europe Framework Programme, PAS GRAS (Grant agreement n. 101080329).

Conflict of interest disclosure: All the authors declare that they have no conflict of interest.

Ethics approval statement: The protocol followed the principles of the Declaration of Helsinki and received approval from the Ethics Committee of Associação Protectora dos Diabéticos de Portugal (APDP Diabetes Portugal (900/2013)) and NOVA Medical School (CEFCM/02/2020), as well as from the Portuguese Data Protection Authority (permit no. 3228/2013).

Patient consent statement: All participants were volunteers and provided written informed consent for inclusion in the PREVADIAB2 cohort analyzed in this paper.

laura.herreranms.unl.pt

maria.menesesnms.unl.pt

rogerio.ribeiroapdp.pt

luis.gardeteapdp.pt

filipe.raposoapdp.pt

jose.boavidaapdp.pt

paula.macedonms.unl.pt

All data presented in this manuscript will be available upon request to collaborative academic researchers for non-profit research purposes only.