Background High Density Lipoproteins (HDL) seem to develop cardioprotective functions beyond the reverse cholesterol transport, thus pointing to their antioxidant activity as a crucial player. Paraoxonase 1 (PON1) is a HDL-associated antioxidant enzyme which has an important role in avoiding lipid oxidization. Although genetic polymorphisms are known to modulate PON1 activity, its involvement in cardiovascular disease (CVD) in Rheumatoid Arthritis (RA) is controversial, suggesting that other factors may modulate its function.
Objectives since anti-HDL antibodies have been related to an impaired lipid profile and CVD in RA, we aimed to evaluate the associations between PON1 activity, anti-HDL antibodies and CVD in RA according to PON1 rs662 genetic variants.
Methods serum PON1 activity, using paraoxon as substrate, and IgG anti-HDL antibodies were quantified in 212 RA patients and 110 healthy controls (HC). The PON1 rs662 genotype (Q>R) was determined with TaqMan probes. An additional group of 13 biologic-naïve RA patients was prospectively followed for three months.
Results PON1 activity was decreased in RA compared to HC (p=0.005). PON1 rs662 variants influenced serum PON1 activity in both groups, QQ homozygotes exhibiting the lowest activity. Distribution of genotypes did not differ between groups (p=0.215) and Hardy-Weinberg equilibrium was observed in both populations. Interestingly, PON1 activity was not associated with disease activity, ESR or CRP. A multivariate ANOVA analysis confirmed an independent role of both rs662 (p<0.0001) and anti-HDL antibodies (p=0.026) on PON1 activity, but differences were noted when patients were stratified by genotypes. Anti-HDL antibodies were associated with an impaired PON1 activity (p=0.010), decreasing HDL levels (r=-0.680, p<0.001) and higher prevalence of CV events in univariate and multivariate models in patients carrying the QQ genotype, but not in their QR or RR counterparts. Finally, change in anti-HDL antibodies upon TNFα-blockade independently predicted improved PON1 activity (B [95% CI], p: -0.369 [-0.669, -0.069], p=0.024) after adjusting by clinical response, change in ESR and change in HDL levels.
Conclusions PON1 activity is impaired in RA in association with rs662 status and anti-HDL antibodies. The presence of anti-HDL antibodies in patients with the low activity genotype was correlated with a decreased PON1 function and associated with a higher prevalence of CV events in these patients. Therefore, anti-HDL antibodies are crucial mediators to understand the link between rs662 polymorphism and CVD.
Disclosure of Interest None declared