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.
RCT Entities:
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-1glutamine 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.
Authors: Christian Besler; Kathrin Heinrich; Lucia Rohrer; Carola Doerries; Meliana Riwanto; Diana M Shih; Angeliki Chroni; Keiko Yonekawa; Sokrates Stein; Nicola Schaefer; Maja Mueller; Alexander Akhmedov; Georgios Daniil; Costantina Manes; Christian Templin; Christophe Wyss; Willibald Maier; Felix C Tanner; Christian M Matter; Roberto Corti; Clement Furlong; Aldons J Lusis; Arnold von Eckardstein; Alan M Fogelman; Thomas F Lüscher; Ulf Landmesser Journal: J Clin Invest Date: 2011-06-23 Impact factor: 14.808
Authors: Mohammed A Hassan; Omar S Al-Attas; Tajamul Hussain; Nasser M Al-Daghri; Majed S Alokail; Abdul K Mohammed; Benjamin Vinodson Journal: Mol Cell Biochem Date: 2013-04-27 Impact factor: 3.396
Authors: Jessica L Mega; Sandra L Close; Stephen D Wiviott; Michael Man; Suman Duvvuru; Joseph R Walker; Scott S Sundseth; Jean-Philippe Collet; Jessica T Delaney; Jean-Sebastien Hulot; Sabina A Murphy; Guillaume Paré; Matthew J Price; Dirk Sibbing; Tabassome Simon; Dietmar Trenk; Elliott M Antman; Marc S Sabatine Journal: J Thromb Thrombolysis Date: 2016-04 Impact factor: 2.300
Authors: W März; M E Kleber; H Scharnagl; T Speer; S Zewinger; A Ritsch; K G Parhofer; A von Eckardstein; U Landmesser; U Laufs Journal: Herz Date: 2016-11-14 Impact factor: 1.443