Relationship of paraoxonase 1 (PON1) gene polymorphisms and functional activity with systemic oxidative stress and cardiovascular risk

Abstract

Context: Paraoxonase 1 (PON1) is reported to have antioxidant and cardioprotective properties. The relationship between PON1 genotypes and functional activity with systemic measures of oxidative stress and cardiovascular disease (CVD) risk in humans has not been systematically investigated.

Objective: To investigate the relationship of genetic and biochemical determinants of PON1 activity with systemic measures of oxidative stress and CVD risk in humans.

Design, setting, and participants: The association between systemic PON1 activity measures and a functional polymorphism (Q192R) resulting in high PON1 activity with prevalent CVD and future major adverse cardiac events (myocardial infarction, stroke, or death) was evaluated in 1399 sequential consenting patients undergoing diagnostic coronary angiography between September 2002 and November 2003 at the Cleveland Clinic. Patients were followed up until December 2006. Systemic levels of multiple structurally defined fatty acid oxidation products were also measured by mass spectrometry in 150 age-, sex-, and race-matched patients and compared with regard to PON1 genotype and activity.

Main outcome measures: Relationship between a functional PON1 polymorphism and PON1 activity with global indices of systemic oxidative stress and risk of CVD.

Results: The PON1 genotype demonstrated significant dose-dependent associations (QQ192 > QR192 > RR192) with decreased levels of serum PON1 activity and with increased levels of systemic indices of oxidative stress. Compared with participants with either the PON1 RR192 or QR192 genotype, participants with the QQ192 genotype demonstrated an increased risk of all-cause mortality (43/681 deaths [6.75%] in RR192 and QR192 and 62/584 deaths [11.1%] in QQ192; adjusted hazard ratio, 2.05; 95% confidence interval [CI], 1.32-3.18) and of major adverse cardiac events (88/681 events [13.6%] in RR192 and QR192 and 102/584 events [18.0%] in QQ192; adjusted hazard ratio, 1.48; 95% CI, 1.09-2.03; P = .01). The incidence of major adverse cardiac events was significantly lower in participants in the highest PON1 activity quartile (23/315 [7.3%]) and 235/324 [7.7%] for paraoxonase and arylesterase, respectively) compared with those in the lowest activity quartile (78/311 [25.1%] and 75/319 [23.5%]; P < .001 for paraoxonase and arylesterase, respectively). The adjusted hazard ratios for major adverse cardiac events between the highest and lowest PON1 activity quartiles were, for paraoxonase, 3.4 (95% CI, 2.1-5.5; P < .001) and for arylesterase, 2.9 (95% CI, 1.8-4.7; P < .001) and remained independent in multivariate analysis.

Conclusion: This study provides direct evidence for a mechanistic link between genetic determinants and activity of PON1 with systemic oxidative stress and prospective cardiovascular risk, indicating a potential mechanism for the atheroprotective function of PON1.

Figure. Relationship Between Functional Genetic and Biochemical Indices of PON1 Activity and Incident Cardiovascular Risk

The paraoxonase 1 (PON1)Q192R genotypes are as follows: RR192 (mutant homozygous); QR192 (heterozygous); and QQ192 (wild type). In the top panels, log-rank P values are shown for the at-risk genotype QQ192 vs RR192 + QR192. PON1 activity (paraoxonase and arylesterase) were categorized into quartiles; Q1: lowest activity quartile; Q4: highest activity quartile. For paraoxonase, Q4>1640, Q3=1640-899.1, Q2=899-450, and Q1<450nmol/min/mL. For arylesterase, Q4>403.9, Q3=403.9-338.5, Q2=338.4-283, and Q1<283 µmol/min/mL In the middle and bottom panels, log-rank P values across activity quartiles are shown. Days indicates number of days from enrollment to first cardiac event. Event rates were calculated at 6-month intervals. Y-axis scales in blue indicate range from 0% to 15%. MI indicates myocardial infarction; CVA, cerebrovascular accident.