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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

Jakub J. Regieli, MD^_*,, J. Wouter Jukema, MD, PhD^,,||,_*, Pieter A. Doevendans, MD, PhD^_*, Aeilko H. Zwinderman, PhD^#, John J. Kastelein, MD, PhD^_**, Diederick E. Grobbee, MD, PhD and Yolanda van der Graaf, MD, PhD

^_* Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands
Juliuscenter for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
Interuniversity Cardiology Institute of the Netherlands (ICIN/KNAW), Leiden, the Netherlands
Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands
^|| Durrer Center for Cardiogenetic Research, Amsterdam, the Netherlands
^# Department of Clinical Epidemiology, Academical Medical Center Amsterdam, Amsterdam, the Netherlands
^_** Department of Vascular Medicine, Academical Medical Center Amsterdam, Amsterdam, the Netherlands

Manuscript received February 18, 2009; revised manuscript received May 4, 2009, accepted May 27, 2009.

^_* Reprint requests and correspondence: Dr. J. Wouter Jukema, Department of Cardiology C5-P, Leiden University Medical Center, P.O. Box 9600, Leiden 2300 RC, the Netherlands (Email: j.w.jukema{at}lumc.nl).

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

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