PON1 Q192R and Clopidogrel: A Case of the Winner’s Curse or Inadequate Replication?

Talameh, Jasmine A.; McLeod, Howard L.

doi:10.1038/clpt.2011.226

Cited by 7 publications

(5 citation statements)

References 15 publications

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“…Experiments establishing the mechanism of GATM involvement with SIM are necessary and could shed light on the specific conditions, if any, in which GATM affects SIM. If a clear mechanism cannot be established, then the findings by Mangravite et al (2013) could have been another case of the “winner’s curse.” The “winner’s curse” is a common phenomenon in genetic association literature, in which the initial reported genotype–phenotype association is exaggerated relative to the estimated effect in follow-up studies or cannot subsequently be replicated at all (Talameh and McLeod, 2011; Zollner and Pritchard, 2007). …”

Section: Discussionmentioning

confidence: 99%

GATM Polymorphism Associated with the Risk for Statin-Induced Myopathy Does Not Replicate in Case-Control Analysis of 715 Dyslipidemic Individuals

et al. 2015

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Summary Statin-induced myopathy (SIM) is the most common reason for discontinuation of statin therapy. A polymorphism affecting the gene encoding glycine amidinotransferase (GATM rs9806699 G>A) was previously associated with reduced risk for SIM. Our objective was to replicate the GATM association in a large, multicenter SIM case-control study. Mild and severe SIM cases and age- and gender-matched controls were enrolled. Participants were genotyped, and associations were tested (n=715) using chi-square and logistic regression with consideration for SIM severity and exclusion of subjects with potentially confounding co-medications. The minor allele (A) frequencies of GATM rs9806699 in the controls (n=106), mild SIM (n=324), and severe SIM (n=285) cases were 0.26, 0.28, and 0.29, respectively (p=0.447). The unadjusted odds ratio for the A allele for any SIM (mild or severe) was 1.14 (0.82–1.61; p=0.437), which remained non-significant in all models. Our results do not replicate the association between GATM rs9806699 and SIM.

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Section: Discussionmentioning

confidence: 99%

GATM Polymorphism Associated with the Risk for Statin-Induced Myopathy Does Not Replicate in Case-Control Analysis of 715 Dyslipidemic Individuals

et al. 2015

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“…In our meta-analysis, most of the studies addressing the association of the PON1-Q192R variant with clinical events involved composite endpoints, with a low incidence of stent thrombosis, possibly leading to an underestimation of the clinical importance of the PON1 genotype (Table 1). Another potential bias is ethnic heterogeneity across the different studies, resulting in genetic differences that might have influenced the response to clopidogrel [45]. Drug-drug interactions, mainly via CYP3A4/ 5, are another important issue when analyzing the variability of clopidogrel responsiveness [46].…”

Section: Pon1-q192r Mace and Platelet Reactivity 1247mentioning

confidence: 99%

Influence of the paraoxonase‐1 Q192R genetic variant on clopidogrel responsiveness and recurrent cardiovascular events: a systematic review and meta‐analysis

Reny

Combescure²,

Daali³

et al. 2012

Journal of Thrombosis and Haemostasis

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Summary Background A poor biological response to clopidogrel is associated with an increased risk of major cardiovascular ischemic events (MACE). Paraoxonase 1 (PON1) enzyme activity is modulated by the PON1-Q192R variant (rs662) and was recently suggested to be strongly involved in clopidogrel bioactivation, but the influence of the PON1-Q192R variant on the risk of MACE in clopidogrel-treated patients is controversial. Objectives To determine whether the PON1-Q192R variant influences clopidogrel biological responsiveness and the risk of MACE in patients treated with clopidogrel. Methods Systematic review and meta-analysis of studies of the association between the PON1-Q192R polymorphism and the biological response to clopidogrel and/or the risk of MACE during clopidogrel administration. Results Seventeen studies were included. In the 12 studies of the biological response to clopidogrel (n = 5302 patients), there was no significant difference between 192QQ and 192QR + 192RR subjects, whatever the laboratory method used (global mean standardized difference = 0.10 [−0.06; 0.25], P = 0.22). Eleven studies assessed the risk of MACE, four using a case–control design (n = 2739 patients) and seven a prospective design (n = 5353 patients). Overall, MACE occurred in 19% of patients in case–control studies and in 6% of patients in prospective cohort studies, with no significant difference between 192QQ and 192QR + 192RR patients (OR = 1.28 [0.97; 1.68], P = 0.08). Similar results were obtained when study design was taken into account. Heterogeneity was mainly driven by one publication. Conclusions This meta-analysis suggests that the PON1-Q192R polymorphism has no major impact on the risk of MACE and does not alter the biological response to clopidogrel in clopidogrel-treated patients.

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“…Differences in populations may be the second issue; the frequency of the Q192 allele is somewhat lower in their cohort study (63.9%) than in any of the other studies [21,[23][24][25][26][31][32][33][34][35]. The observed clinical differences between PON1 gene variants may be due to clopidogrel-unrelated mechanisms, as PON1 plays a direct effect on atherogenesis by protecting low-density lipoprotein from oxidation [58]. This may partly explain the trend towards an association of the PON1-Q192R variant with MACE, best seen in four studies in addition to Bouman's studies (Figure 2) [15,20].…”

Section: Discussionmentioning

confidence: 90%

PON-1 Q192R (rs662) Gene Polymorphism and the Risk of Major Adverse Cardiovascular Events in Clopidogrel-Treated Patients with Coronary Heart Disease: A Systematic Review and Meta-Analysis

2018

CACA

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Aims: To determine the association between the PON1 Q192R (rs662) gene polymorphism and the risk of Major Adverse Cardiovascular Events (MACE), especially the risk of Stent Thrombosis (ST), in clopidogreltreated patients with Coronary Heart Disease (CHD). Methods:We searched academic databases, book chapters and proceedings of international meetings for clinical trials investigating the relationship between the PON1 Q192R (rs662) gene polymorphism and the clinical outcome of CHD patients receiving clopidogrel as antiplatelet treatment. The pooled Odds Ratios (ORs) with 95% Confidence Interval (CI) were calculated using the STATA 12.0 software with random-effects model. Results:We identified 18 clinical trials with a total number of 16801 CHD patients, seven using a case-control design (n=3098) and eleven a prospective cohort design (n=13703). Meta-analysis revealed that the PON1 Q192R (rs662) genetic polymorphism was not associated with an increased risk of MACE [

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PON1 Q192R and Clopidogrel: A Case of the Winner’s Curse or Inadequate Replication?

Cited by 7 publications

References 15 publications

GATM Polymorphism Associated with the Risk for Statin-Induced Myopathy Does Not Replicate in Case-Control Analysis of 715 Dyslipidemic Individuals

GATM Polymorphism Associated with the Risk for Statin-Induced Myopathy Does Not Replicate in Case-Control Analysis of 715 Dyslipidemic Individuals

Influence of the paraoxonase‐1 Q192R genetic variant on clopidogrel responsiveness and recurrent cardiovascular events: a systematic review and meta‐analysis

PON-1 Q192R (rs662) Gene Polymorphism and the Risk of Major Adverse Cardiovascular Events in Clopidogrel-Treated Patients with Coronary Heart Disease: A Systematic Review and Meta-Analysis

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