Association of PON1 Gene Promoter DNA Methylation with the Risk of Clopidogrel Resistance in Patients with Coronary Artery Disease

Background And Aims: The 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.

Methods: Through 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.

Results: In 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.

Conclusions: The 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.