Quarterly Focus Issue: Prevention/Outcomes
Coronary Disease Risk
Paraoxonase Variants Relate to 10-Year Risk in Coronary Artery Disease: Impact of a High-Density Lipoprotein–Bound Antioxidant in Secondary Prevention

https://doi.org/10.1016/j.jacc.2009.05.061Get rights and content
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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.

Key Words

ischemic heart disease
prognosis
lipoproteins
genes
epidemiology

Abbreviations and Acronyms

CAD
coronary artery disease
CI
confidence interval
HDL
high-density lipoprotein
HDL-C
high-density lipoprotein cholesterol
HR
hazard ratio
IHD
ischemic heart disease
L
leucine
LDL
low-density lipoprotein
LDL-C
low-density lipoprotein cholesterol
M
methionine
MI
myocardial infarction
PON
paraoxonase
Q
glutamine
R
arginine
TG
triglycerides

Cited by (0)

Drs. Jukema and Kastelein are established clinical investigators of the Netherlands Heart Foundation. Dr. Kastelein is a consultant for all pharmaceutical companies that produce low-density lipoprotein lowering medication. The original REGRESS trial was sponsored by Bristol-Myers Squibb, New York. The current work was supported by grants from the Netherlands Organisation for Health Research and Development (AGIKO grant 920-03-367 to Dr. Regieli and program grant 904-65-095 to Drs. Regieli, Grobbee, and van der Graaf) and the Interuniversity Cardiology Institute of the Netherlands (project number 15 to Drs. Jukema and Zwinderman), and by the Bekalis Foundation (Dr. Doevendans). These funding sources had no involvement in the writing of this paper or its submission.