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

Q: What is the clinical evidence from this study?

Study design: Cohort. Population: Dysglycemia and metabolic liver risk (Fibrotic NASH Index >0.1) (n=922). Intervention: PON1 C–A haplotype (rs854572 C – rs2057681 A) in rs2057681 GA/GG carriers vs. PON1 G–A haplotype (rs854572 G – rs2057681 A) in rs2057681 GA/GG carriers. Primary outcome: Prevalence of dysglycemia in individuals aged >55 years carrying at least one rs2057681 G allele (RR 0.68, 95% CI 0.48-0.95, p=0.025).

Q: What does this research mean for the field?

Specific PON1 haplotypes, defined by promoter-transcribed region interactions, are associated with dysglycemia and metabolic liver risk in a genotype-dependent manner that is independent of steady-state paraoxonase enzyme activity. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Laura Batista-Herrera; Maria João Meneses; Rogério T. Ribeiro; L. Gardete-Correia; João F. Raposo; José Manuel Boavida; Carlos Penha-Gonçalves; Maria Paula Macedo

doi:10.3389/fendo.2026.1870186

July 7, 2026Frontiers in EndocrinologyOpen Access

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

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Key result

PON1 C–A haplotype linked to ~32% lower dysglycemia prevalence in older G-allele carriers.

RR 0.68
95% CI 0.48-0.95
P=0.025
n=922

Why the study?

Do PON1 promoter–transcribed region haplotypes (rs854572–rs2057681) influence serum paraoxonase activity, dysglycemia, and elevated metabolic liver risk (FNI >0.1) in adults aged >55 years?

Study Design

Type

Cohort (n=922)

Structured PICO

Do PON1 promoter–transcribed region haplotypes (rs854572–rs2057681) influence serum paraoxonase activity, dysglycemia, and elevated metabolic liver risk (FNI >0.1) in adults aged >55 years?

P

Population

922 individuals from the Portuguese PREVADIAB2 cohort (879 after genetic filtering), with clinical outcome analyses of dysglycemia and metabolic liver risk restricted to participants aged >55 years.

E

Exposure

PON1 genetic variants (specifically coding-region intronic variant rs2057681 tagging Q192R and promoter variant rs854572) and their phased promoter–transcribed region haplotypes (specifically the C–A haplotype vs other configurations, stratified by rs2057681 GA/GG or AA genotype background)

C

Comparator

Reference PON1 G–A haplotype (rs854572 G allele and rs2057681 A allele) within the respective rs2057681 genotype stratum (GA/GG carriers or AA homozygotes)

O

Outcome

Serum paraoxonase (PONase) enzymatic activity, prevalence of dysglycemia (prediabetes and diabetes defined by WHO/IDF criteria via fasting glucose and 75 g OGTT), and elevated metabolic liver risk defined as Fibrotic NASH Index (FNI) >0.1 in individuals aged >55 yearssurrogate

Main Result

Relative Risk: 0.68 (95% CI 0.48–0.95)

Absolute Event Rate: 27.2% vs 42.2%

p-value: p=0.025

Limitations

Conducted in a single population-based cohort with moderate analytical sample size for stratified analyses, requiring replication in independent populations
Metabolic liver risk was assessed using a surrogate marker (Fibrotic NASH Index) rather than imaging or histological assessment
Residual confounding by lifestyle factors, medication use, and other metabolic indicators cannot be excluded
Serum PONase activity was the only functional PON1 readout available, without assays of arylesterase/lactonase activity or circulating PON1 protein levels
Restriction of clinical outcome analyses to individuals aged >55 years limits generalizability to younger populations
Single population-based cohort with moderate sample size in genotype- and haplotype-stratified analyses, requiring external replication
Metabolic liver risk was estimated using a surrogate index (Fibrotic NASH Index) rather than liver imaging or histology
Potential residual confounding from unmeasured lifestyle factors, medication use, and other metabolic indicators
Only serum paraoxonase (PONase) activity was measured, lacking arylesterase activity, lactonase activity, HDL functionality, or PON1 protein concentration assays
Restriction of dysmetabolic outcome analyses to individuals aged >55 years limits generalizability to younger age groups

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Implication

PON1 promoter–transcribed region haplotypes associate with dysglycemia and metabolic liver risk in a genotype-context-dependent manner independent of steady-state serum paraoxonase activity, helping explain prior inconsistent cardiometabolic associations of single PON1 variants.

Abstract

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.

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Cite This Study

Batista-Herrera et al. (2026) conducted a cohort in Dysglycemia and metabolic liver risk (Fibrotic NASH Index >0.1) (n=922). PON1 C–A haplotype (rs854572 C – rs2057681 A) in rs2057681 GA/GG carriers vs. PON1 G–A haplotype (rs854572 G – rs2057681 A) in rs2057681 GA/GG carriers was evaluated on Prevalence of dysglycemia in individuals aged >55 years carrying at least one rs2057681 G allele (RR 0.68, 95% CI 0.48-0.95, p=0.025). The PON1 C–A haplotype was associated with lower dysglycemia prevalence (RR 0.68, 95% CI 0.48-0.95) and metabolic liver risk (RR 0.74) in rs2057681 G-allele carriers aged >55 years.

synapsesocial.com/papers/6a5966842275dee03afc7811 https://doi.org/10.3389/fendo.2026.1870186

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

Study Design

Structured PICO

Main Result

Limitations

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Implication

Abstract

Discussion

Cite This Study

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

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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