Background/Purpose: Rheumatoid arthritis (RA) has a pre-clinical state. In particular, elevation of antibodies to citrullinated proteins (ACPA) is a strong risk factor for future clinically-apparent inflammatory arthritis that can be termed ‘clinical RA’, however not all ACPA+ individuals who are ‘at-risk’ develop clinical RA. Furthermore, we have limited understanding into which factors drive the transition from preclinical to clinical RA. Paraoxonase-1 (PON1) is an HDL-associated enzyme which metabolizes pro-inflammatory oxidized lipids. We have previously shown that increasing PON1 activity over time is associated with decreased risk of incident clinical RA in ACPA+ at-risk individuals (ARI) (Razmjou, et al. ACR Abstract #464, 2024). The PON1 Q192R polymorphism (rs662) has been shown to affect PON1 enzyme activities. This study aimed to investigate if the PON1 Q192R polymorphism associates with incident clinical RA in an ACPA+ ARI population.

Methods: ACPA+ (determined by the anti-CCP3 assay) ARI who did not have clinical RA at baseline were evaluated; 49 (37%) of whom developed clinical RA during longitudinal follow-up. PON1 Q192R polymorphism (‘Q192R’) were tested as previously described (Charles-Schoeman, et al. J Rheumatol, 2023). PON1 activity was measured as previously described (Charles-Schoeman, et al. Sci Rep, 2020) by its paraoxonase, lactonase, and arylesterase enzymatic functions. Cox-proportional hazards models were used to evaluate the effect of Q192R on time to clinical RA, with multivariate models including variables with p-values < 0.05 in univariate models. Q192R was analyzed as an ordinal variable (0, 1, or 2 R alleles), and a categorical variable (QR or RR v QQ, ref QQ).

Results: The baseline characteristics of ACPA+ ARI are in Table 1. A greater proportion of ARI with QR, and RR genotypes developed clinical RA (Figure 1). In univariate Cox-proportional hazards models with Q192R, the # of R alleles and RR vs QQ were significantly associated with increased risk of developing clinical RA over time. Significance was maintained in multivariable models after including shared epitope (SE) positivity, and RF IgA/IgM positivity (Table 2). Multivariable models including change in PON1 enzyme activity, SE, RF IgA/IgM, age, sex and BMI also showed that increased # of R alleles were associated with an elevated risk of clinical RA (p < 0.05) (Table 2).

Conclusion: In a population of ACPA+ ARI, the PON1 Q192R genotype was significantly associated with increased risk of developing clinical RA, even after controlling for the presence of SE and RF positivity as well as PON1 activity. PON1 activity by lactonase function was inversely associated with the development of clinical RA. Future studies include validating these findings in additional cohorts and incorporating these findings into predictive models for future clinical RA, as well as evaluating the mechanisms of the effect of the PON1 Q192R polymorphism on clinical RA development.

Values are mean (SD) or N (%)

*p < 0.05

PON values are baseline values at first sample, divided by 10.

Significance testing done by Student’s T-test for continuous variables, and Chi-Square test for categorical variables.

RA: rheumatoid arthritis, BMI: body mass index, RF: rheumatoid factor, IgA: immunoglobulin A, IgM: immunoglobulin M, PON1: paraoxonase-1, QQ/QR/RR: PON1 Q192 R genotype polymorphisms (rs662).

Legend: ***p < 0.001. Brackets are 95% CI. Percents and numbers represent participants with, and without clinical RA within each of the 3 PON1 genotypes. RA: rheumatoid arthritis, cRA: clinical RA, PON1: paraoxonase-1, QQ/QR/RR: PON1 Q192 R genotype polymorphisms (rs662).

*p < 0.05

%Multivariate model includes PON1 Q192R genotype (# of R alleles), shared epitope positivity and RF isotypes (IgA/IgM), and. # of R Alleles: QQ=0, QR=1, RR=2.

#Multivariate models include PON1 Q192R genotype (categorical variable QR or RR vs QQ), shared epitope positivity and RF isotypes (IgA/IgM),.

^Multivariate models include PON1 Q192R genotype (# of R alleles), respective change of PON1 activity since last visit (PON, LAC, or ARYL), RF isotypes (IgA/IgM), shared epitope positivity, and age, gender, and BMI (age/gender/BMI included due to known relevance in PON1 activity).

%#Models were chosen by step-wise regression of different predictors (including age, BMI, gender which were not significant). Shared epitope was included in the model due to its known biologic importance.

RA: rheumatoid arthritis, PON1: paraoxonase-1, QQ/QR/RR: PON1 Q192 R genotype polymorphisms (rs662), RF: rheumatoid factor, IgA: immunoglobulin A, IgM: immunoglobulin M, PON: paraoxonase activity, LAC: lactonase activity, ARYL: arylesterase activity.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-paraoxonase-1-q192r-polymorphism-is-associated-with-increased-risk-of-incident-clinical-rheumatoid-arthritis-in-an-anti-citrullinated-protein-antibody-positive-population/