Paraoxonase variants relate to 10-year risk in coronary artery disease: impact of a high-density lipoprotein–bound antioxidant in secondary prevention
JJ Regieli, JW Jukema, PA Doevendans… - Journal of the American …, 2009 - jacc.org
JJ Regieli, JW Jukema, PA Doevendans, AH Zwinderman, JJ Kastelein, DE Grobbee…
Journal of the American College of Cardiology, 2009•jacc.orgObjectives: We investigated the effects of paraoxonase (PON)-1 variants on long-term
clinical outcome in patients with coronary artery disease (CAD). Background: PON-1 is a
potential therapeutic target to further reduce cardiovascular risk because it is a detoxifying
esterase with antioxidant properties. The PON-1 knockout models result in higher
susceptibility to atherosclerosis, and PON activity contributes to cardiovascular risk in
humans. Human gene variants determine PON activity; however, the impact of these …
clinical outcome in patients with coronary artery disease (CAD). Background: PON-1 is a
potential therapeutic target to further reduce cardiovascular risk because it is a detoxifying
esterase with antioxidant properties. The PON-1 knockout models result in higher
susceptibility to atherosclerosis, and PON activity contributes to cardiovascular risk in
humans. Human gene variants determine PON activity; however, the impact of these …
Objectives
We investigated the effects of paraoxonase (PON)-1 variants on long-term clinical outcome in patients with coronary artery disease (CAD).
Background
PON-1 is a potential therapeutic target to further reduce cardiovascular risk because it is a detoxifying esterase with antioxidant properties. The PON-1 knockout models result in higher susceptibility to atherosclerosis, and PON activity contributes to cardiovascular risk in humans. Human gene variants determine PON activity; however, the impact of these variants on recurrent cardiovascular events in vascular disease is as of yet unknown.
Methods
We conducted a 10-year follow-up study of 793 CAD patients in the REGRESS (REgression GRowth Evaluation Statin Study) trial cohort, using nationwide registries. Genotypes were obtained of 2 PON-1 isotypes (L55M, rs854560, and Q192R, rs662), which were previously associated with PON activity. Absolute and relative risks by genotype were estimated using Kaplan-Meier and proportional hazards analyses.
Results
Carriership of the PON-1 glutamine isotype at codon 192 and methionine at codon 55 was associated with a higher risk of death due to ischemic heart disease. Hazard ratios per allele copy were 1.71 (95% confidence interval: 1.0 to 2.8, p = 0.03) for the glutamine isotype at codon 192 and 1.56 (95% confidence interval: 1.1 to 2.3, p = 0.03) for methionine at codon 55. Both isotypes had previously been related to lower PON activity. No effect was observed on all-cause mortality.
Conclusions
PON-1 gene variants influence the 10-year risk of fatal complications from CAD in male patients, despite no effect on all-cause mortality. These long-term findings confirm functional data on PON-1 activity, emphasize the relevance of this pathway in vascular disease, and enforce its putative role as a target to modify and estimate cardiovascular risk.
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