Dataset Information

The impact of P2Y12 promoter DNA methylation on the recurrence of ischemic events in Chinese patients with ischemic cerebrovascular disease.

ABSTRACT: The primary mechanism of clopidogrel resistance is still unclear. We aimed to investigate whether the methylation status of the P2Y12 promoter has effects on platelet function and clinical ischemic events. Patients with ischemic cerebrovascular disease were enrolled into our study. Venous blood samples were drawn for thrombelastograpy (TEG) and active metabolite assay. Patients were divided into a case- or control-group based on the occurrence of ischemic events during a one year follow-up. Two TEG parameters between the case and control groups were statistically significant [ADP inhibition rate (ADP%): P?=?0.018; ADP-induced platelet-fibrin clot strength (MA_ADP): P?=?0.030]. The concentrations of clopidogrel active metabolite had no significant difference (P?=?0.281). Sixteen CpG dinucleotides on P2Y12 promoter were tested. Three CpG sites (CpG11 and CpG12?+?13) showed lower methylation status, which correlated with a strong association with increased risk of clinical events. Changes of MA_ADP and ADP% were also associated with methylation levels of CpG 11 and CpG 12?+?13. Hypomethylation of the P2Y12 promoter is associated with a higher platelet reactivity and increased risk of ischemic events in our patients. Methylation analysis of peripheral blood samples might be a novel molecular marker to help early identification of patients at high risk for clinical ischemic events.

SUBMITTER: Li XG

PROVIDER: S-EPMC5043343 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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The impact of P2Y12 promoter DNA methylation on the recurrence of ischemic events in Chinese patients with ischemic cerebrovascular disease.

Li Xin-Gang XG Ma Ning N Wang Bo B Li Xiao-Qing XQ Mei Sheng-Hui SH Zhao Kun K Wang Yong-Jun YJ Li Wei W Zhao Zhi-Gang ZG Sun Shu-Sen SS Miao Zhong-Rong ZR

Scientific reports 20160930

The primary mechanism of clopidogrel resistance is still unclear. We aimed to investigate whether the methylation status of the P2Y12 promoter has effects on platelet function and clinical ischemic events. Patients with ischemic cerebrovascular disease were enrolled into our study. Venous blood samples were drawn for thrombelastograpy (TEG) and active metabolite assay. Patients were divided into a case- or control-group based on the occurrence of ischemic events during a one year follow-up. Two ...[more]

PMID: 27686864

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Project description:One pending issue in cardiovascular epigenetics is whether cerebrovascular events, a major complication of atherosclerosis, are associated with any specific DNA methylation changes in the carotid plaque. To clarify that topic, we profiled the DNA methylomes of human symptomatic carotid plaques (SCPs) obtained from patients who suffered cerebrovascular events (n=19) and asymptomatic counterparts (ACP; n=19) with a high-density microarray (~485,000 CpG sites, Illumina), and crossed DNA methylation data with RNAseq-based expression data from an independent SCP set (n=8). Few (30) CpGs showed a significant (p<0.05; absolute Delta-Beta>0.20) differential methylation between the two groups. Within SCPs, methylation correlated significantly with post-cerebrovascular event time (PCET; range: 3-45 days; r-value range -0.926 to 0.857; p<0.05) for ~45,000 CpGs, the vast majority of which became hypomethylated with increasing PCET. Hypomethylation was not due to erasure of the gene-body and CG-poor region hypermethylation that accompany the progression of stable lesions, but rather targeted promoters and CpG islands. Noticeably, promoter hypomethylation and increased expression were observed for genes involved in the inhibition of the inflammatory response, defence against oxidative stress and active DNA demethylation. Our data show that only weak changes in the DNA methylome distinguish symptomatic from asymptomatic carotid plaques, but a widespread demethylation resulting in permissive transcriptional marks at atheroprotective gene promoters is established in plaques after a cerebrovascular event, thus mirroring previous observations that ruptured plaques tend to revert to a more stable structure. The identified loci are candidate targets to accelerate the pace of carotid plaque stabilization. DNA was quantified by Quant-iT PicoGreen dsDNA Reagent (Invitrogen) and the integrity was analyzed in a 1.3% agarose gel. Bisulfite conversion of 600 ng of each sample was perform according to the manufacturer's recommendation for Illumina Infinium Assay. Effective bisulphite conversion was checked for three controls that were converted simultaneously with the samples. 4 ul of bisulfite converted DNA were used to hybridize on Infinium HumanMethylation 450 BeadChip, following Illumina Infinium HD Methylation protocol. Chip analysis was performed using Illumina HiScan SQ fluorescent scanner. The intensities of the images are extracted using GenomeStudio (2011.2) Methylation module (1.8.5) software. Methylation score of each CpG is represented as beta value.

Project description:Background Studies have shown that pericoronary artery inflammation can be accurately detected via increased attenuation on computed tomography. Our purpose was to evaluate the association between pericarotid inflammation, measured by density of carotid perivascular fat on computed tomography angiography, with stroke and transient ischemic attack. Methods and Results We screened computed tomography angiography examinations for patients with unilateral internal carotid artery ( ICA ) stenosis ?50% to 99%. A blinded neuroradiologist placed regions-of-interest in the pericarotid fat on the slice showing maximal stenosis. Two-sample t tests were performed to assess between-subject differences in mean Hounsfield Units in carotid perivascular fat between symptomatic and asymptomatic patients. Paired t tests were used to assess within-subject differences in mean Hounsfield Units between stenotic versus nonstenotic ICA s in a given patient. We included 94 patients, including 42 symptomatic and 52 asymptomatic patients. In the between-subject analysis of stenotic ICA s, we found symptomatic patients had higher mean pericarotid fat density compared with asymptomatic patients (-66.2±19.2 versus -77.1±20.4, P=0.009). When comparing nonstenotic ICA s, there was no significant difference between pericarotid fat density in symptomatic compared with asymptomatic patients (-81.0±13.3 versus -85.3±18.0: P=0.198). Within-subject comparison showed statistically significant increased density in stenotic ICA versus nonstenotic ICA with mean Hounsfield Units difference of 11.1 ( P<0.0001). Conclusions We found increased density, a surrogate marker for perivascular inflammation, in the fat surrounding ICA s ipsilateral to stroke or transient ischemic attack compared with asymptomatic ICA s. Our findings suggest that inflammation associated with culprit carotid plaques extends beyond the vessel lumen and can be identified using simple methods on computed tomography angiography imaging.

Dataset Information

The impact of P2Y12 promoter DNA methylation on the recurrence of ischemic events in Chinese patients with ischemic cerebrovascular disease.

Publications

The impact of P2Y12 promoter DNA methylation on the recurrence of ischemic events in Chinese patients with ischemic cerebrovascular disease.

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