Abstract 294: Gene Variants Conferring High Paraoxonase Activity Decrease 10 Year Cardiovascular Risk In Coronary Artery Disease.
INTRODUCTION Paraoxonase(PON)-1 is a potential therapeutic target to further reduce cardiovascular risk, since it is a detoxifying esterase with anti-atherogenic properties. PON1 knockout models result in increased LDL oxidation in-vitro and higher susceptibility to atherosclerosis in vivo. Human gene variants encoding 55-Leucine(L) to Methionine(M) and 192-Glycine(Q) to Arginine(R) substitutions, are strong determinants of physiological PON1 activity in vitro. Activity is elevated with L55 and R192, however the impact on cardiovascular outcomes is yet unknown. We investigated the effect of these variants on 10 year outcomes in patients with CAD.
METHODS Long term mortality of the REGRESS cohort comprising 884 male CAD patients was derived from nation-wide registries. Endpoints were defined from recorded ICD codes. Genotypes of L55M and Q192R were obtained in 791(89%) 794 (90%) participants respectively. Risks according to genotype were estimated using proportional hazard analyses.
RESULTS Death related to ischemic heart disease (IHD) occurred in 58 (6.6%) patients, overall death in 149 patients(17%). Genotype distributions were 325 (41%) LL, 352 (45% ) LM, 114 (14%) MM and 420 (28 %) QQ, 287 (55 %) QR, 87 (17 %) RR. Hazard Ratios were 0.59 (0.36 – 0.96),p=0.03 for R192, and 1.57 (1.1–2.3), p=0.03 for M55 (see figure⇓) per each allele copy.
DISCUSSION Paraoxonase gene variants 55M and 192Q confer an increased 10-year risk of IHD related death in CAD patients. These long-term findings confirm functional data on PON-1 activity, emphasize the relevance of this pathway in atherogenesis, and enforce its putative role as a target to modify and estimate vascular risk.