Association of PON1 gene promoter DNA methylation with the risk of Clopidogrel resistance in patients with coronary artery disease

Abstract

Background and AimsThe failure of therapeutic response to clopidogrel in platelet inhibition, which is called clopidogrel resistance (CR), is more likely to cause cardiovascular events. We aimed to study the contribution of promoter DNA methylation of paraoxonase 1 (PON1) to the risk of clopidogrel poor response.MethodsThrough VerifyNow P2Y12 assay, patient’ platelet functions were measured. Among 57 non‐CR and 49 CR patients, the levels of DNA methylation in four CpG dinucleotides on the PON1 promoter were tested using bisulfite pyrosequencing technology. Besides, the relative expression of PON1 mRNA was analyzed by quantitative real‐time PCR. Logistic regression was applied to investigate the interaction of PON1 methylation and clinical factors in CR.ResultsIn the subgroup with dyslipidemia, we discovered that higher CpG4 levels of the PON1 promoter indicated a poorer clopidogrel response (cases versus controls (%): 51.500 ± 14.742 vs 43.308 ± 10.891, P = 0.036), and the PON1 mRNA expression was reduced in CR patients. Additionally, the logistic regression indicated that higher level of albumin and the index of ALT were related to a lower risk of CR, and the index of AST as well as the quantity of stent may be positively associated with CR.ConclusionsThe DNA methylation of CpG4 in the PON1 promoter would lead to a low expression of PON1 mRNA, which might induce clopidogrel resistance in the patients with dyslipidemia, and the number of stents might be a risk for CR.

The impact of cytochrome 450 and Paraoxonase polymorphisms on clopidogrel resistance and major adverse cardiac events in coronary heart disease patients after percutaneous coronary intervention

“…Clopidogrel is a prodrug, it needs to be metabolized into an active metabolite with the activity of cytochrome P450 and paraoxonase to playing the role of antiplatelet aggregation (9). The variants of cytochrome P450 and paraoxonase can lead to the change of enzyme activity, especially the mutation of CYP2C19*2, CYP2C19*3, PONQ192R allelic [17,18]. The probe drug could be used to measure the activity of CYP450 and to point out the genotyping of CYP450 [19].…”

Association ofGCKgene DNA methylation with the risk of clopidogrel resistance in acute coronary syndrome patients

“…A recent investigation reported that aberrant DNA methylation might participate in the occurrence and development of atherosclerotic plaques and coronary heart disease . Furthermore, some studies have demonstrated that changes in ABCB1, ABCC3, P2Y12, and PON1 promoter methylation levels were associated with a decline in clopidogrel antiplatelet effects.…”

“…26 and coronary heart disease. 27 Furthermore, some studies have demonstrated that changes in ABCB1, 28 ABCC3, 29 P2Y12, 17 and PON1 18 promoter methylation levels were associated with a decline in clopidogrel antiplatelet effects.…”

“…Additionally, if GCK DNA methylation changes, then glucose homeostasis in F1 offspring would be disrupted after maternal bisphenol A exposure . Although our former studies showed that the DNA methylation of P2Y12 and PON1 might be associated with CR, the effect of GCK DNA methylation on CR is not clearly understood. In this study, in ACS patients with clopidogrel treatment, we attempted to explore whether the selected CpG islands methylation in GCK is associated with CR.…”

The Role of CYP450 Drug Metabolism in Precision Cardio-Oncology

“…It is hypothesized that epigenetic modifications in the promotor or coding region, in response to certain physiologic or pathophysiologic states, can either activate or silence certain CYP450 enzymes. For example, methylation of CpG motifs (CpG11, CpG12, CpG13) in the promoter region for CYP2C19 was associated with HTPR and increased risk of ischemic events on clopidogrel [7,85,86]. If an allele is preferentially silenced via epigenetic modifications in the coding region, the complementary allele will be predominantly expressed.…”