ABCMdb

ABCB1 p.Ala576Gly

Predicted by SNAP2:	C: N (57%), D: D (75%), E: D (71%), F: D (53%), G: D (63%), H: D (66%), I: N (97%), K: D (71%), L: N (61%), M: N (57%), N: D (63%), P: D (75%), Q: D (63%), R: D (66%), S: D (53%), T: N (57%), V: N (93%), W: D (71%), Y: D (63%),
Predicted by PROVEAN:	C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: N, W: D, Y: D,

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[hide] Effect of paraoxonase-1 polymorphism on clinical o... Clin Pharmacol Ther. 2011 Oct;90(4):561-7. doi: 10.1038/clpt.2011.193. Epub 2011 Sep 14. 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., [PMID:21918510]

Abstract [show]
Paraoxonase-1 (PON1) Q192R polymorphism was recently suggested to determine per se clopidogrel response on major cardiovascular events (MACEs). We assessed the impact of PON1, CYP2C19, and ABCB1 polymorphisms on MACE in clopidogrel-treated acute myocardial infarction (AMI) patients (N = 2,210), including those undergoing percutaneous coronary intervention (PCI) (n = 1,538). PON1 polymorphism was not associated with increased risk of in-hospital death and MACEs at 1 year (adjusted hazard ratio (HR) 1.03, 95% confidence interval (CI) 0.66-1.61 and adjusted HR 0.77, 95% CI 0.42-1.41 for QQ versus RR in all and PCI patients, respectively). The presence of two CYP2C19 loss-of-function (LOF) alleles was associated with the risk of in-hospital death and MACEs at 1 year in the overall population (adjusted odds ratio (OR) 3.67, 95% CI 1.05-12.80 and adjusted HR 1.96, 95% CI 1.08-3.54) and in PCI patients (adjusted OR 6.87, 95% CI 2.52-18.72 and adjusted HR 3.06, 95% CI 1.47-6.41). Unlike CYP2C19 polymorphism, PON1 (Q192R) polymorphism is not a major pharmacogenetic contributor of clinical response to clopidogrel in AMI patients.

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4 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 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 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 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 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 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 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 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 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 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 In-hospital events were analyzed with logistic regression analyses according to PON1 A576G genotype. Login to comment

[hide] Genetic determinants of on-clopidogrel high platel... Platelets. 2011;22(6):399-407. doi: 10.3109/09537104.2011.579648. Epub 2011 May 31. Campo G, Miccoli M, Tebaldi M, Marchesini J, Fileti L, Monti M, Valgimigli M, Ferrari R
Genetic determinants of on-clopidogrel high platelet reactivity.
Platelets. 2011;22(6):399-407. doi: 10.3109/09537104.2011.579648. Epub 2011 May 31., [PMID:21627411]

Abstract [show]
Clopidogrel has been used (alone or in association with aspirin) to prevent vascular complications in atherothrombotic patients, to prevent stent thrombosis (ST) in patients undergoing percutaneous coronary intervention (PCI) and as a long-term prevention of cardiovascular and cerebrovascular events. Unfortunately, it is important to note that there are a number of patients who, during clopidogrel therapy, show and maintain a high platelet reactivity (PR), similar to that observed before the start of antiplatelet therapy. Clopidogrel pro-drug is absorbed in the intestine and this process is influenced by P-glycoprotein-1 (P-GP). Its conversion into 2-oxo clopidogrel is regulated by cytochromes (CYP) called CYP2C19, CYP2B6 and CYP1A2. Whereas, the final transformation into the active metabolite is regulated by CYP called CYP2C19, CYP2C9, CYP2B6, CYP3A4, CYP3A5 and, as recently emerged, by the glycoprotein paraoxonase-1 (PON1). The genes encoding these enzymes are characterized by several polymorphisms. Some of these are able to modify the activity of proteins, reducing the concentration of active metabolite and the values of on-clopidogrel PR. Only one gene polymorphism (CYP2C19*17) increases the clopidogrel metabolization and so the clopidogrel-induced platelet inhibition. Several studies have clearly associated these gene polymorphisms to both ischemic and bleeding complications in patients receiving dual antiplatelet therapy. The aim of this review is to describe the principal gene polymorphisms influencing on-clopidogrel PR and their relationship with long-term clinical outcome.

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118 However, the most frequent and studied is the A576G in which an adenine is replaced with a guanine in exon 6. Login to comment