DNA methylation of MMPs and TIMPs in atherothrombosis process in carotid plaques and blood tissues
Por:
Gallego-Fabrega C., Cullell N., Soriano-Tárraga C., Carrera C., Torres-Aguila N.P., Muiño E., Cárcel-Márquez J., de Moura M.C., Fernández-Sanlés A., Esteller M., Elosua R., Jiménez-Conde J., Roquer J., Montaner J., Krupinski J., Fernandez-Cadenas I.
Publicada:
10 mar 2020
Ahead of Print:
10 mar 2020
Resumen:
Background and Purpose: Polymorphisms and serum levels of Matrix Metalloproteinases (MMP) and Tissue Inhibitor of Metalloproteinases (TIMP) have been studied with regard to atheromatous plaques and ischemic stroke, while no studies of DNA methylation (DNAm) patterns of MMP or TIMP have been performed to that end. Here, we evaluate DNAm levels of the MMP and TIMP gene families in human carotid plaques and blood samples of atherothrombotic stroke patients. Methods: We profiled the DNAm status of stable and ulcerated atherosclerotic plaques obtained as pair sets from three patients who underwent carotid endarterectomy surgery. We selected 415 CpG sites, mapping into MMPs and TIMPs genes for further study. Secondly, the statistically associated CpG sites were analyzed in blood samples from two separate atherothrombotic stroke cohorts (total sample size = 307), ischemic stroke-cohort 1 (ISC-1): 37 atherothrombotic patients and 6 controls, ischemic stroke-cohort 2 (ISC-2): 80 atherothrombotic patients and 184 controls. DNAm levels from plaque tissue and blood samples were evaluated using a high-density microarray Infinium, HumanMethylation450 BeadChip and Infinium MethylationEPIC BeadChip. Results: Three CpG sites were statistically significantly associated with unstable plaque portions; cg02969624, q-value = 0.035 (TIMP2), and cg04316754, q-value = 0.037 (MMP24) were hypermethylated, while cg24211657 q-value = 0.035 (TIMP2) was hypomethylated. Association of cg04316754 (MMP24) methylation levels with atherothrombotic risk was also observed in blood tissue: ISC-1 p-values = 0.03, ISC-2 p-value = 1.9 × 10-04. Conclusions: The results suggest different DNAm status of MMP24 between stable and unstable atherothrombotic carotid plaques, and between atherothrombotic stroke and controls in blood samples. © Copyright: Gallego-Fabrega et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Filiaciones:
Gallego-Fabrega C.:
Neurology, Hospital Universitari Mútua de Terrassa, Fundacio Docència i Recerca MutuaTerrassa, Terrassa, Spain
Stroke Pharmacogenomics and Genetics, Sant Pau Research Institute, Barcelona, Spain
Cullell N.:
Neurology, Hospital Universitari Mútua de Terrassa, Fundacio Docència i Recerca MutuaTerrassa, Terrassa, Spain
Stroke Pharmacogenomics and Genetics, Sant Pau Research Institute, Barcelona, Spain
Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain
Soriano-Tárraga C.:
Department of Neurology, Hospital del Mar, Neurovascular Research Group, Institut Hospital del Mar d'Investigacions Mèdiques, Universitat Autònoma de Barcelona, DCEXS-Universitat Pompeu Fabra, Barcelona, Spain
Carrera C.:
Stroke Pharmacogenomics and Genetics, Sant Pau Research Institute, Barcelona, Spain
Neurovascular Research Laboratory, Vall d'Hebron Institute of Research, Universitat Autònoma de Barcelona, Barcelona, Spain
Torres-Aguila N.P.:
Stroke Pharmacogenomics and Genetics, Sant Pau Research Institute, Barcelona, Spain
Muiño E.:
Stroke Pharmacogenomics and Genetics, Sant Pau Research Institute, Barcelona, Spain
Cárcel-Márquez J.:
Stroke Pharmacogenomics and Genetics, Sant Pau Research Institute, Barcelona, Spain
de Moura M.C.:
Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Spain
Fernández-Sanlés A.:
Cardiovascular Epidemiology and Genetics Research Group, Hospital del Mar Medical Research Institute, Universitat Pompeu Fabra, Barcelona, Spain
Esteller M.:
Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Spain
Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Spain
Institucio Catalana de Recerca i Estudis Avançats, Barcelona, Spain
Elosua R.:
Cardiovascular Epidemiology and Genetics Research Group, Hospital del Mar Medical Research Institute, Universitat Pompeu Fabra, Barcelona, Spain
Jiménez-Conde J.:
Department of Neurology, Hospital del Mar, Neurovascular Research Group, Institut Hospital del Mar d'Investigacions Mèdiques, Universitat Autònoma de Barcelona, DCEXS-Universitat Pompeu Fabra, Barcelona, Spain
Roquer J.:
Department of Neurology, Hospital del Mar, Neurovascular Research Group, Institut Hospital del Mar d'Investigacions Mèdiques, Universitat Autònoma de Barcelona, DCEXS-Universitat Pompeu Fabra, Barcelona, Spain
Montaner J.:
Neurovascular Research Laboratory, Vall d'Hebron Institute of Research, Universitat Autònoma de Barcelona, Barcelona, Spain
Krupinski J.:
Neurology, Hospital Universitari Mútua de Terrassa, Fundacio Docència i Recerca MutuaTerrassa, Terrassa, Spain
Centre for Biomedicine, Manchester Metropolitan University, Manchester, United Kingdom
Fernandez-Cadenas I.:
Stroke Pharmacogenomics and Genetics, Sant Pau Research Institute, Barcelona, Spain
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