Paraoxonase variants relate to 10-year risk in coronary artery disease: impact of a high-density lipoprotein-bound antioxidant in secondary prevention.
OBJECTIVE
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.
Regieli
Jakub J
JJ
Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.
Jukema
J Wouter
JW
Doevendans
Pieter A
PA
Zwinderman
Aeilko H
AH
Kastelein
John J
JJ
Grobbee
Diederick E
DE
van der Graaf
Yolanda
Y
D043303:Aryldialkylphosphatase / Q000235:genetics*; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D003062:Codon; D005500:Follow-Up Studies; D005787:Gene Frequency; D005838:Genotype; D005973:Glutamine / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008297:Male; D008715:Methionine / Q000235:genetics; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000235:genetics* / Q000401:mortality*; D011110:Polymorphism, Genetic; D016016:Proportional Hazards Models; D012907:Smoking / Q000453:epidemiology; D014280:Triglycerides / Q000097:blood
D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D003062:Codon; D014280:Triglycerides; D005973:Glutamine; D008715:Methionine; D043303:Aryldialkylphosphatase