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PON1 haplotypes show genotype-dependent associations with dysglycemia and metabolic liver risk beyond paraoxonase activity

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dc.contributor.authorBatista-Herrera, Laura
dc.contributor.authorMeneses, Maria João
dc.contributor.authorRibeiro, Rogério T.
dc.contributor.authorGardete-Correia, Luís
dc.contributor.authorRaposo, João F.
dc.contributor.authorBoavida, José Manuel
dc.contributor.authorPenha-Gonçalves, Carlos
dc.contributor.authorMacedo, Maria Paula
dc.contributor.institutioniNOVA4Health - pólo NMS
dc.contributor.institutionNOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
dc.contributor.institutionVector borne diseases and pathogens (VBD)
dc.contributor.institutionGlobal Health and Tropical Medicine (GHTM)
dc.contributor.institutionLaboratório Associado de Translacção e Inovação para a Saúde Global - LA Real (Pólo IHMT)
dc.contributor.institutionInstituto de Higiene e Medicina Tropical (IHMT)
dc.contributor.pblFrontiers Media
dc.date.accessioned2026-09-07T15:21:01Z
dc.date.available2026-09-07T15:21:01Z
dc.date.issued2026
dc.descriptionPublisher Copyright: Copyright © 2026 Batista-Herrera, Meneses, Ribeiro, Gardete-Correia, Raposo, Boavida, Penha-Gonçalves and Macedo.
dc.description.abstractIntroduction – 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.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent3513682
dc.identifier.doi10.3389/fendo.2026.1870186
dc.identifier.issn1664-2392
dc.identifier.otherPURE: 171588574
dc.identifier.otherPURE UUID: 7707a171-7d1e-471b-8bc7-2b16a960d504
dc.identifier.otherScopus: 105046060019
dc.identifier.otherORCID: /0000-0002-2549-0275/work/226046699
dc.identifier.urihttp://hdl.handle.net/10362/206141
dc.identifier.urlhttps://www.scopus.com/pages/publications/105046060019
dc.language.isoeng
dc.peerreviewedyes
dc.subjectdysglycemia
dc.subjectgenetic epidemiology
dc.subjectmetabolic liver disease
dc.subjectoxidative stress
dc.subjectparaoxonase
dc.subjectPON1
dc.subjectEndocrinology, Diabetes and Metabolism
dc.subjectSDG 3 - Good Health and Well-being
dc.titlePON1 haplotypes show genotype-dependent associations with dysglycemia and metabolic liver risk beyond paraoxonase activityen
dc.typejournal article
degois.publication.titleFRONTIERS IN ENDOCRINOLOGY
degois.publication.volume17
dspace.entity.typePublication
rcaap.rightsopenAccess

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