2227: The Paraoxonase-1 Q192R Polymorphism is Associated with Increased Risk of Incident Clinical Rheumatoid Arthritis in an Anti-Citrullinated Protein Antibody-Positive Population

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.