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

Abstract

Backgrounds Clopidogrel resistance (CR), which was manifested as the failure of platelet inhibition in clopidogrel treatment, was likely to lead to cardiovascular events. Our study was aimed to explore the contribution of DNA methylation in glucokinase (GCK) to the CR risk. Methods Among 36 CR and 36 non‐CR acute coronary syndrome (ACS) patients, the platelet functions were evaluated by VerifyNow P2Y12 assay (turbidimetric‐based optical detection) and DNA methylation levels on two fragments of the CGI from the GCK were investigated through bisulfite pyrosequencing methods. In addition, the GCK mRNA expression was analyzed via quantitative real‐time PCR. Lastly, the logistic regression was employed to test the interaction between GCK methylation and nongenetic variables in CR patients. Results Subunit analysis showed that in male patients without DM but suffering from dyslipidemia, the increased methylation of cg18492943 indicated a risk of poor clopidogrel response (male, NCR vs CR(%): 84.86 ± 6.29 vs 88.16 ± 4.32, P = .032; without DM, NCR vs CR (%): 84.66 ± 6.18 vs 88.16 ± 4.17, P = .029; and dyslipidemia, NCR vs CR (%): 83.81 ± 6.96 vs 88.39 ± 4.74, P = .042).In addition, GCK mRNA expression was reduced in CR patients without DM. Moreover, regression analysis indicated that the values of platelet distribution width (PDW), total cholesterol (TC), and uric acid (UA) were correlated with the incidence of CR, and hypertension lowered the CR risk. Conclusions A higher methylation of cg18492943 in GCK gene would lower the expression of GCK mRNA, which might contribute to CR in patients without DM. Meanwhile, PDW and TC might be risk factors in CR.

The association of polymorphisms in related circadian rhythm genes and clopidogrel resistance susceptibility

“…DNA methylation might be another novel molecular marker for the identification of higher platelet reactivity. Previous studies indicate that methylation levels of the P2Y12 , 38 PON1 39 and GCK 17 promoter might be related to a decline in clopidogrel response. One study also pointed out that P2Y12 promoter hypomethylation correlates with higher platelet activity and a poor risk of ischaemic events 40 .…”

“…The participants of this study were selected from this cohort, and they provided informed written consent. According to our previous research, 17 the patients who fulfilled the criteria were enrolled in our database. The inclusion criteria were as follows: (1) according to the recent ACC/AHA guidelines, ACS patients who underwent PCI using drug‐eluting stents, with most having multi‐vessel disease of the coronary arteries or left main vessel disease; (2) patients who were administered 300‐mg aspirin and 300‐mg clopidogrel as a loading dose before PCI and received 100‐mg aspirin and 75‐mg clopidogrel daily as a maintenance dose; (3) all the patients were administered pantoprazole to protect the gastrointestinal bleeding; patients were older than 18 years, and (4) without aspirin resistance (ARU less than 550).…”

Polymorphisms in the GCK gene increase the risk of clopidogrel resistance in stable coronary artery disease (SCAD) patients

“…Usually, the DNA hypermethylation [25], and another study indicated that P2Y12 promoter hypomethylation was correlate to higher platelet-activity and a poor risk for ischaemic events [26]. Former studies also indicated that methylation levels of P2Y12 [27], PON1 [28], and GCK [29] promoter might be relative to a decline in clopidogrel responding. Additionally, clinical pharmacokinetics research revealed that hypomethylation of the PON1 promoter may be a risk factor for bleeding after dual antiplatelet therapy [30].…”

“…GCK (located at 7p15.3-p15.1) encodes a glucose enzyme and catalyses the committed step of insulin secretion, balances glucose homeostasis and regulates glycogen synthesis [7]. Our former study revealed that the higher methylation of cg18492943 would lower the GCK mRNA expression, leading to high platelet activity in non-DM patients [8].…”

PON1 Q192R is associated with high platelet reactivity with clopidogrel in patients undergoing elective neurointervention: A prospective single-center cohort study

“…A recent report demonstrated that lower platelet count was associated with larger mean platelet volume, which reflected greater prothrombotic activity [ 32 ]. Another report demonstrated an association between total cholesterol level and clopidogrel resistance [ 33 ]. However, these associations remain controversial and the mechanism is unclear.…”