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PLoS One. 2013;8(2):e52779.

Paraoxonase 1 gene polymorphism does not affect clopidogrel response variability but is associated with clinical outcome after PCI.

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제1저자 박경우 · 교신저자 김효수

PMID 23418418 PMC3572125 DOI 10.1371/journal.pone.0052779 IF 2.8 순환기내과
소속 (1)
  1. Department of Internal Medicine and Cardiovascular Center, Seoul National University Hospital, Seoul, Korea.

Abstract

BACKGROUND Paraoxonase (PON) is a high-density-lipoprotein (HDL) associated enzyme with antioxidative and anti-atherogenic property. Its function is associated with coronary artery disease and its activity genetically controlled. We evaluated whether genetic variation of PON-1 is associated with clinical outcome in a large cohort of Korean patients with drug-eluting stents implantation.

METHODS A total of 1676 patients with drug-eluting stent implantation were enrolled in the prospective CROSS-VERIFY cohort from June 2006 to June 2010. We genotyped the PON1-Q192R gene, measured clopidogrel on-treatment platelet reactivity (OPR), and analyzed lipid profiles. The primary endpoint was the composite of cardiac death, myocardial infarction, and stent thrombosis at 12 months.

RESULTS PON-1 genotyping data were available in 1336 patients. Since the Q-allele is associated with decreased PON-activity, we analyzed the outcome between patients with QQ/QR (815 patients, 61%) and those with RR-genotype (521 patients, 39%). After adjustment for common cardiac risk factors, the QQ/QR-genotype was an independent predictor of the primary thrombotic endpoint with an 11-fold increased risk (HR 11.6, 95% CI: 1.55-87.0), but not repeat revascularization (HR 1.12, 95% CI: 0.78-1.61). The QQ/QR-genotype was not associated with OPR (QQ/QR: 231±86 PRU vs. RR 236±82 PRU, p = 0.342) but higher small-dense LDL levels (1.20±0.12 mg/dL vs. 0.76±0.15 mg/dL, p = 0.027). The increased risk of thrombotic outcomes was more profound in acute coronary syndrome (ACS) patients compared with non-ACS patients.

CONCLUSION PON1 Q-allele is an independent predictor of worse cardiovascular outcome independent of platelet function and is associated with significantly higher levels of small dense LDL-C.

Figures

Figure 1
Figure 1 Kaplan-Meier curves for primary composite end point of cardiac death, myocardial infarction, and stent thrombosis. Patients with PON-1 QQ/QR genotypes had higher rates for primary endpoint than those with RR-genotype (2.2% vs. 0.2%, Log-rank p = 0.002) (Fig. 1A). This difference in thrombotic outcomes was more profound in the higher risk ACS patients compared with the lower risk non-ACS patients (3% vs. 0%, Log-rank p = 0.008) (Fig. 1B), although the trend toward higher risk of thrombotic outcome in the QQ/QR group was maintained even in the non-ACS group (1.7% vs. 0.3%, Log-rank p = 0.098) (Fig. 1C).
Figure 2
Figure 2 Kaplan-Meier curves for target lesion revascularization. There was no difference in target lesion revascularization rates between PON-1 QQ/QR and RR genotypes either in all patients (9.8% vs. 9.0%, Log-rank P = 0.546) (Fig. 2A), in those with ACS presentation (8.4% vs. 10%, Log rank P = 0.271) (Fig. 2B), or those with non-ACS-presentation (10.8% vs. 8.2%, Log-rank P = 0.224) (Fig. 2C).
Figure 3
Figure 3 On-treatment platelet reactivity (OPR) according to PON1-Q192R genotypes. There was no difference in OPR between QQ, QR, and RR genotypes (mean OPR: 233±82 PRU, 231±86 PRU, and 236±81 PRU, for QQ, QR, and RR genotypes respectively, ANOVA P = 0.596).
Figure 4
Figure 4 Lipid profiles according to genotypes. Patients with QQ/QR genotypes had lower triglyceride levels (Fig. 4A). As for LDL particle size, there was no difference either in VLDL, IDL between both groups (Fig. 4B), or large and medium sized LDL (Fig. 4C). As for small LDL, patients with QQ/QR genotype had significant higher LDL-IIIA than those RR-genotype (1.20±0.12 mg/dL vs. 0.76±0.15 mg/dL, P = 0.027) (Fig. 4D). Cholesterol level was compared by using one-way ANOVA test. As for LDL-particle size, general linear model analysis was applied to quantify the effect of PON-1 QQ/QR genotype on LDL-particle size after adjustment for age, sex, triglyceride level, HDL-C level, and statin use. Data were presented as the mean ± the SEM.

그림 출처: PubMed Central 공개 논문 (PMC3572125)

Conflict of interest statement

Competing Interests:The authors have declared that no competing interests exist.

그 밖의 정보
출판 형태
Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
저널
PloS one · eISSN 1932-6203
전자 출판
2013-02-13
MeSH
Aged · Aged, 80 and over · Aryldialkylphosphatase / genetics · Clopidogrel · Coronary Artery Disease / drug therapy / genetics / surgery · Female · Genotype · Humans · Male · Middle Aged · Percutaneous Coronary Intervention* · Pharmacogenetics · Platelet Aggregation Inhibitors / therapeutic use · Polymorphism, Genetic · Prospective Studies · Risk Factors · Stents · Ticlopidine / analogs & derivatives / therapeutic use
Substances
Platelet Aggregation Inhibitors · Clopidogrel · Aryldialkylphosphatase · Ticlopidine
연구비
PHS HHS A062260 · PHS HHS A102065
참고문헌
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