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PPM1A Methylation Is Associated With Vascular Recurrence in Aspirin-Treated Patients
Cristina Gallego-Fabrega1, Caty Carrera1, Jean-Luc Reny1
1From the Stroke Pharmacogenomics and Genetics, Fundació Docència i Recerca MutuaTerrassa, Hospital Mútua de Terrassa, Terrassa, Spain (C.G.-F., E.M., N.C., I.F.-C.); School of Medicine, University of Barcelona, Barcelona, Spain (C.G.-F.); Neurovascular Research Laboratory, Vall d'Hebron Institute of Research, Universitat Autonoma de Barcelona, Barcelona, Spain (C.C., J.M.); Division of Internal Medicine and Rehabilitation (J.-L.R.) and Division of Angiology and Haemostasis (P.F.), Geneva University Hospitals, Switzerland; Geneva Platelet Group, Faculty of Medicine, Geneva, Switzerland (J.-L.R., P.F.); Department of Neurology, Jagiellonian University Medical College, Krakow, Poland (A.S., J.P.); Dipartimento di Scienze Cliniche e Sperimentali, Clinica Neurologica, Università degli Studi di Brescia, Brescia, Italy (A.P.); Neurology Department, Albacete Hospital, Albacete, Spain (G.S.-H., T.S.); College of Applied Medical Sciences, Majmaah University, Saudi Arabia (A.-A.A.B.D.); Department of Neurology, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain (J.M.-F.); Neurology Service, Hospital Universitari Mútua Terrassa, Terrasa, Spain (J.K.); and School of Healthcare Science, Manchester Metropolitan University, Manchester, UK (J.K.).
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.
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