Increase in the risk of clopidogrel resistance and consequent TIMI flow impairment by DNA hypomethylation of CYP2C19 gene in STEMI patients undergoing primary percutaneous coronary intervention (PPCI)

Abstract

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Association between GNAQ Gene DNA Methylation and Vascular Recurrence in Patients with Acute Ischemic Stroke or Transient Ischemic Attack

“…Yang et al [25] compared the whole genomic methylation patterns of blood samples and found that the CR and non-CR showed significantly different DNA methylation at 7,098 sites, with 979 sites showing hypermethylation and 6,119 sites showing hypomethylation. Sukmawan et al [26] investigated the role of CYP2C19 gene DNA methylation for CR in ST-elevation MI patients undergoing primary percutaneous coronary intervention and found that DNA methylation level percentage was significantly lower in the CR group than in clopidogrel responder group. Su et al [14] found the aberrant methylation DNA methylation of CR patients in the ABCB1, P2Y12 [15], and PON1 genes [12].…”

Clinical and Pharmacological Parameters Determine Relapse During Clopidogrel Treatment of Acute Coronary Syndrome

“…50 Moreover, the diabetic state also affects profoundly the epigenetic landscape, possibly altering the expression of genes whose products alter clopidogrel pharmacokinetics and pharmacodynamics. 19,20,51 Diabetics are, therefore, a population of patients at high risk of recurrent thrombotic events even under clopidogrel therapy. 32,33,52,53 Type 2 diabetes, especially the insulin-dependent type, was strongly associated with disease relapse in our study.…”

“…Physiologically, patients with type 2 diabetes mellitus are characterized by a prothrombotic status favored by resistance to antithrombotic physiological signals, shear‐induced aggregation, nonenzymatic glycation of platelet glycoproteins, changes in the structure and conformation of platelets, increased oxidative stress, and increased platelet turnover 50 . Moreover, the diabetic state also affects profoundly the epigenetic landscape, possibly altering the expression of genes whose products alter clopidogrel pharmacokinetics and pharmacodynamics 19,20,51 …”

“…18 Additionally, beyond specific germinal genetic variants, recent efforts have been directed to identify epigenetic footprints that may alter the expression of genes whose products may be related or are likely to be involved in the response to clopidogrel. 19,20 When testing pharmacokinetic and pharmacodynamic parameters of clopidogrel in young, healthy subjects, the interindividual variability seem to be unpredictable based on a single parameter, so clinical resistance is likely dependent on multiple factors beyond specific genotypes, including pharmacological interactions with other drugs and associated comorbidities. 21 Early studies have associated the use of proton pump inhibitors and calcium channel blockers (CCBs) with a reduced antiplatelet response ex vivo and decreased clinical efficacy of clopidogrel, 22,23 but there is no conclusive evidence of clinical relevance to date.…”

“…A recent report predicts that a compound pharmacogenomic polygenic response score, encompassing allelic variation at multiple genes that are associated with increased on‐treatment platelet reactivity, is able to generate a risk profile as the number of variants increases 18 . Additionally, beyond specific germinal genetic variants, recent efforts have been directed to identify epigenetic footprints that may alter the expression of genes whose products may be related or are likely to be involved in the response to clopidogrel 19,20 …”