ABCMdb

PMID: 21918510

Simon T, Steg PG, Becquemont L, Verstuyft C, Kotti S, Schiele F, Ferrari E, Drouet E, Grollier G, Danchin N
Effect of paraoxonase-1 polymorphism on clinical outcomes in patients treated with clopidogrel after an acute myocardial infarction.
Clin Pharmacol Ther. 2011 Oct;90(4):561-7. doi: 10.1038/clpt.2011.193. Epub 2011 Sep 14., [PubMed]

Sentences

No. Mutations Sentence Comment

4 ABCB1 p.Ala576Gly The metabolism of clopidogrel is a two-step oxidative process.9 The presence of a CYP2C19 loss-of-function (LOF) genetic variant has been associated in numerous studies with reduced concentrations of active clopidogrel metabolite, diminished platelet inhibition, and higher rates of adverse cardiovascular events in patients treated with clopidogrel, particularly among acute coronary syndrome patients undergoing PCI.6,12-16 However, a recent study has suggested that the second step of the metabolism involves a hydrolytic cleavage rather than an oxidation process.10 The authors found that CYP450 enzymes are not involved in the second metabolic step, whereas paraoxonase-1 (PON1), an esterase synthesized in the liver and associated with high-density lipoproteins in blood, mediates the bioactivation of the 2-oxo-clopidogrel intermediate to the active thiol metabolite.10 Additionally, when treated with clopidogrel, patients who were AA (QQ) homozygotes for PON1 A576G 1Assistance Publique-Hôpitaux de Paris (APHP), Hôpital St. Login to comment 11 ABCB1 p.Ala576Gly Using data from the French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI),11 in which a patient subset provided samples for genetic analysis,6 we assessed the association between the PON1 A576G (Q192R) polymorphisms and adverse cardiovascular outcomes during treatment with clopidogrel in patients with acute myocardial infarction (AMI) and among the subset of AMI patients undergoing PCI. Login to comment 15 ABCB1 p.Ala576Gly The 2,170 patients treated with clopidogrel who both provided a genetic sample and had PON1 A576G (Q192R) genotyped were included in this analysis. Login to comment 20 ABCB1 p.Ala576Gly Risk of in-hospital events and 1-year outcomes according to PON1 genotype In the overall genotyped patients receiving clopidogrel, the PON1 A576G genotype was not associated with the risk of in-hospital ischemic events (Table2 and Supplementary Figure S1 online). Login to comment 26 ABCB1 p.Ala576Gly When we examined the in-hospital events, the risk of events in QQ or QR Table 1 Baseline characteristics (n (%) unless otherwise stated) of the overall genotyped AMI population treated by clopidogrel PON1 A576G (Q192R) AA (QQ) AG (QR) GG (RR) (n = 999) (n = 1,011) (n = 200) Age (years, mean ± SD) 66 ± 14 66 ± 13 65 ± 15 Sex (women) 306 (31) 292 (29) 52 (26) BMI (kg/m2, mean ± SD) 27.0 ± 4.9 27.3 ± 4.6 26.9 ± 4.2 Hypertension 585 (59) 573 (57) 121 (61) Diabetes mellitus 304 (30) 334 (33) 58 (29) Hyperlipidemia 487 (49) 520 (51) 84 (42)* Current smoking 310 (31) 322 (32) 59 (30) Peripheral artery disease 99 (10) 94 (9) 15 (8) Family history 232 (23) 238 (24) 57 (29) Priorhistoryof MI 167 (17) 177 (18) 29 (15) PCI 139 (14) 146 (14) 26 (13) CABG 54 (5) 53 (5) 11 (6) Heart failure 36 (4) 53 (5) 5 (3) Stroke 40 (4) 49 (5) 14 (7) Priortreatmentwith Clopidogrel 134 (13) 152 (15) 20 (10) Aspirin 238 (24) 225 (22) 44 (22) β-Blockers 229 (23) 244 (24) 52 (26) Statins 283 (28) 295 (29) 36 (18) ACE inhibitors 202 (20) 190 (19) 32 (16) GRACE score 161 ± 36 163 ± 36 161 ± 38 Treatmentwithin48h Aspirin 923 (92) 938 (93) 185 (92.5) β-Blockers 718 (72) 734 (73) 150 (75) Statins 774 (78) 808 (80) 157 (79) ACE inhibitors 458 (46) 505 (50) 97 (49) ARBs 77 (8) 67 (7) 12 (6) Ca2+ channel blockers 207 (21) 170 (17) 38 (19) *P < 0.05. Login to comment 45 ABCB1 p.Ala576Gly Table 3 In-hospital and 1-year major outcomes in the genotyped PCI population treated by clopidogrel according toPON1 genotype PON1 A576G (Q192R) AA (QQ) AG (QR) GG (RR) Pn = 660 n = 733 n = 145 In-hospitaldeath,MI,orstroke, n (%) 21 (3.2) 27 (3.7) 8 (5.5) Adjusted OR, model 1 (95% CI) 0.60 (0.23-1.56) 0.63 (0.25-1.62) 1 0.56 Adjusted OR (95% CI)a 0.59 (0.22-1.58) 0.68 (0.26-1.77) 1 0.58 Death,MI,orstrokeat1year, n (%) 54 (8.2) 72 (9.8) 15 (10.3) Adjusted HR, model 1 (95% CI) 0.77 (0.42-1.41) 0.72 (0.40-1.31) 1 0.56 Adjusted HR (95% CI)a 0.74 (0.40-1.36) 0.71 (0.39-1.29) 1 0.52 Death,MI,orstrokeat1yearinhospital survivors, n (%) 42 (6.7%) 56 (8.0%) 11 (8.2%) Adjusted HR, model 2 (95% CI) 0.68 (0.35-1.30) 0.68 (0.36-1.30) 1 0.47 Adjusted HR (95% CI)b 0.65 (0.33-1.25) 0.67 (0.35-1.28) 1 0.41 Model 1: adjusted for age, sex, cardiovascular risk factors, GRACE score, history of stroke, peripheral vascular disease, heart failure, comorbidities, type of MI, reperfusion therapy, Killip class on admission, medications used before current episode, medications and procedures used during first 48 h. Model 2: model 1 + in-hospital bleeding or transfusion, in-hospital recurrent infarction, and discharge medications. Login to comment 50 ABCB1 p.Ala576Gly The results of our study showed the absence of association between PON1 A576G (Q192R) polymorphism and the occurrence of any major ischemic events in patients after AMI. Login to comment 60 ABCB1 p.Ala576Gly However, there are other intriguing results in the study by Bouman et al.10 A PON1 A576G (Q192R) gene polymorphism was found to be related to clopidogrel pharmacokinetics, platelet response, and a threefold increased risk of stent thrombosis. Login to comment 79 ABCB1 p.Ala576Gly In conclusion, PON1 A576G (Q192R) polymorphism was not associated with the incidence of major ischemic events in AMI patients during hospitalization or at 1-year follow-up in the overall cohort, hospital survivors, or PCI patients. Login to comment 94 ABCB1 p.Ala576Gly On the basis of a previous study,10 patients were classified according to PON1 A576G genotype as homozygous for the A allele (AA), heterozygous (AG), or homozygous for the G allele (GG). Login to comment 109 ABCB1 p.Ala576Gly In-hospital events were analyzed with logistic regression analyses according to PON1 A576G genotype. Login to comment