PPM1A Methylation Is Associated With Vascular Recurrence in Aspirin-Treated Patients

Abstract

Background and Purpose— Despite great efforts by pharmacogenetic studies, the causes of aspirin failure to prevent the recurrence of ischemic events remain unclear. Our aim was to study whether epigenetics could be associated with the risk of vascular recurrence in aspirin-treated stroke patients. Methods— We performed an epigenetic joint analysis study in 327 patients treated with aspirin. In the discovery stage, we performed a nested case–control study in 38 matched ischemic stroke patients in whom 450 000 methylation sites were analyzed. Nineteen patients presented vascular recurrence after stroke, and 19 matched patients did not present vascular recurrence during the first year of follow-up. In a second stage, 289 new patients were analyzed by EpiTYPER. Results— The following 3 differentially methylated candidate CpG sites, were identified in the discovery stage and analyzed in the second stage: cg26039762 ( P =9.69×10 −06 , RAF1 ), cg04985020 ( P =3.47×10 −03 , PPM1A ), and cg08419850 ( P =3.47×10 −03 , KCNQ1 ). Joint analysis identified an epigenome-wide association for cg04985020 ( PPM1A ; P =1.78×10 −07 ), with vascular recurrence in patients treated with aspirin. Conclusions— The pattern of differential methylation in PPM1A is associated with vascular recurrence in aspirin-treated stroke patients.

Pathogenesis of Ischemic Stroke: Role of Epigenetic Mechanisms

“…Hypermethylation of ApoE cerebrovascular diseases [61]. The hypomethylation of TNF receptor-associated factor 3 (TRAF3) and of protein phosphatase 1A (PPM1A) is also related to increased stroke occurrence in patients treated with antiplatelet drugs [62,63]. and VCAM-1 expression may be considered as an early event in the etiology of cardiovascular and cerebrovascular diseases [61].…”

“…and VCAM-1 expression may be considered as an early event in the etiology of cardiovascular and cerebrovascular diseases [61]. The hypomethylation of TNF receptor-associated factor 3 (TRAF3) and of protein phosphatase 1A (PPM1A) is also related to increased stroke occurrence in patients treated with antiplatelet drugs [62,63]. Atherosclerotic cerebral infarction [56,57] Stroke patients Hypermethylation of CDKN2B prevalent ischemic heart disease or stroke.…”

“…The latter evidence suggests that the association between LINE hypomethylation and VCAM-1 expression may be considered as an early event in the etiology of cardiovascular and cerebrovascular diseases [61]. The hypomethylation of TNF receptor-associated factor 3 (TRAF3) and of protein phosphatase 1A (PPM1A) is also related to increased stroke occurrence in patients treated with antiplatelet drugs [62,63]. it is rapidly expressed in pro-atherosclerotic conditions [59,60].…”

“…The hypomethylation of TNF receptor-associated factor 3 (TRAF3) and of protein phosphatase 1A (PPM1A) is also related to increased stroke occurrence in patients treated with antiplatelet drugs [62,63]. Stroke occurrence [62,63] Legend:…”

The Management of Cardiovascular Risk through Epigenetic Biomarkers

“…DNA methylation in specific genes can also be helpful to predict response to a specific treatment. Two elegant studies by Gallego-Fabrega et al have shown that changes in DNA methylation patterns of PPM1A and TRAF3 are, respectively, associated with vascular recurrence in aspirin-treated patients and clopidogrel response and recurrence of ischemic events in patients with stroke [25, 26]. …”