Background/Purpose:

Paraoxonase 1 (PON1) is a high density lipoprotein (HDL) associated enzyme, which promotes the anti-oxidant and anti-inflammatory properties of HDL. PON1 polymorphisms and enzyme activity have previously been associated with cardiovascular (CV) events in the general population. The current work investigated the relationship of genetic and biochemical determinants of PON1 activity with progression of carotid atherosclerosis (ATH) in a longitudinal cohort of patients with rheumatoid arthritis (RA).

Methods: Carotid ultrasounds were performed at 2 time points separated by a mean ± SD of 5.6 ± 1.2 years on a longitudinal cohort of 149 RA patients at a single academic center. The number and type of carotid plaques were assessed and an ATH score provided by the same radiologist for all scans. Fasting blood was collected for lipoprotein analysis and inflammatory markers done by standard assays, and PON1 activity was measured using paraoxon as the substrate. Genotyping for the PON1 Q192R polymorphism (SNP rs662) was done for all patients as described previously (Arthritis Rheum. 2013 Nov;65(11):2765-72). Traditional cardiovascular risk factors, medication use, and RA disease characteristics were assessed for all patients at baseline and follow-up visits.

Results:

The PON1 genotype demonstrated a significant dose dependent association with PON1 activity (RR192 > QR192 > QQ192) (p≤0.003) at baseline and follow-up visits. Compared to patients with either the PON1 RR192 or QR192 genotype, patients with the QQ192 genotype demonstrated increased risk of carotid plaque progression measured by ≥ one unit increase in carotid ATH score in multivariate analysis controlling for significant traditional CV risk factors, RA disease characteristics, medication use, and the presence of carotid plaque on baseline ultrasound (p<0.05). Similar results were noted when defining ATH progression by ≥ one new carotid plaque from the baseline scan. Separate multivariate logistic regression analysis controlling for the same significant RA and traditional CV risk factors also revealed a significant association of mean plasma PON1 activity with carotid ATH progression in RA patients. Lower mean plasma PON1 activity was associated with increased risk of carotid ATH progression as assessed both by ≥ one unit increase in carotid ATH score, or by ≥ one new carotid plaque from the baseline study in individual multivariate models (p <0.05). Mean total, LDL, and HDL cholesterol levels were not associated with carotid ATH progression in this cohort.

Conclusion:

The current work suggests a relationship between the genetic determinants and activity of PON1 with cardiovascular risk in RA patients as assessed by the progression of carotid ATH over 5 year longitudinal follow-up. Further CV outcome studies may be warranted to determine if PON1 is a useful biomarker of CV risk in patients with RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/association-of-paraoxonase-1-gene-polymorphisms-and-enzyme-activity-with-progression-of-carotid-atherosclerosis-in-rheumatoid-arthritis/