Clinical and Genetic Association of Serum Paraoxonase and Arylesterase Activities With Cardiovascular Risk
Arteriosclerosis, Thrombosis, and Vascular Biology
Objective—Diminished serum paraoxonase and arylesterase activities (measures of paraoxonase-1 [PON-1] function) in humans have been linked to heightened systemic oxidative stress and atherosclerosis risk. The clinical prognostic use of measuring distinct PON-1 activities has not been established, and the genetic determinants of PON-1 activities are not known. Methods and Results—We established analytically robust high-throughput assays for serum paraoxonase and arylesterase activities and measured these in 3668 stable subjects undergoing elective coronary angiography without acute coronary syndrome and were prospectively followed for major adverse cardiovascular events (MACE= death, myocardial infarction, stroke) over 3 years. Low serum arylesterase and paraoxonase activities were both associated with increased risk for MACE, with arylesterase activity showing greatest prognostic value (quartile 4 versus quartile 1; hazard ratio 2.63; 95% CI, 1.97–3.50; P<0.01). Arylesterase remained significant after adjusting for traditional risk factors, C-reactive protein, and creatinine clearance (hazard ratio, 2.20; 95% CI, 1.60–3.02; P<0.01), predicted future development of MACE in both primary and secondary prevention populations, and reclassified risk categories incrementally to traditional clinical variables. A genome-wide association study identified distinct single nucleotide polymorphisms within the PON-1 gene that were highly significantly associated with serum paraoxonase (1.18×10-303) or arylesterase (4.99×10−116) activity but these variants were not associated with either 3-year MACE risk in an angiographic cohort (n=2136) or history of either coronary artery disease or myocardial infarction in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis consortium (n≈80 000 subjects). Conclusion—Diminished serum arylesterase activity, but not the genetic determinants of PON-1 functional measures, provides incremental prognostic value and clinical reclassification of stable subjects at risk of developing MACE.
Tang, W.H. Wilson; Hartiala, Jaana; Fan, Yiying; Wu, Yuping; Stewart, Alexandre F.R.; Erdmann, Jeanette; Kathiresan, Sekar; Cardiogram Consortium, Lerner Research Institute; Roberts, Robert; McPherson, Ruth; Allayee, Hooman; and Hazen, Stanley L., "Clinical and Genetic Association of Serum Paraoxonase and Arylesterase Activities With Cardiovascular Risk" (2012). Mathematics Faculty Publications. 173.
This research was supported by National Institutes of Health grants P01HL076491-055328, 5P01HL103453, and the Fondation Leducq. The GeneBank study has been supported by National Institutes of Health grants P01HL098055, R01HL103866, 1P20HL113452, 1R01HL103931, R01ES021801 (Dr Allayee), and the Cleveland Clinic Clinical Research Unit of the Case Western Reserve University Clinical and Translational Sciences Award (UL1TR 000439-06). Dr Hazen is also partially supported by a gift from the Leonard Krieger Fund. The John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre investigators are supported by Canadian Institutes of Health Research (CIHR) #Medical Research Council Operating Grant Program (MOP)-82810, Canada Foundation for Innovation (CFI) #11966, Heart and Stroke Foundation of Ontario (HSFO) #NA6001, CIHR #MOP172605, and CIHR #MOP77682.