Research Papers:

DNA methylation of MMPs and TIMPs in atherothrombosis process in carotid plaques and blood tissues

Cristina Gallego-Fabrega _, Natalia Cullell, Carolina Soriano-Tárraga, Caty Carrera, Nuria P. Torres-Aguila, Elena Muiño, Jara Cárcel-Márquez, Manuel Castro de Moura, Alba Fernández-Sanlés, Manel Esteller, Roberto Elosua, Jordi Jiménez-Conde, Jaume Roquer, Joan Montaner, Jerzy Krupinski _ and Israel Fernandez-Cadenas _

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Cristina Gallego-Fabrega1,2, Natalia Cullell1,2,3, Carolina Soriano-Tárraga4, Caty Carrera2,5, Nuria P. Torres-Aguila2, Elena Muiño2, Jara Cárcel-Márquez2, Manuel Castro de Moura6, Alba Fernández-Sanlés7, Manel Esteller6,8,9, Roberto Elosua7, Jordi Jiménez-Conde4, Jaume Roquer4, Joan Montaner5, Jerzy Krupinski1,10,* and Israel Fernandez-Cadenas2,*

1 Neurology, Hospital Universitari Mútua de Terrassa/Fundacio Docència i Recerca MutuaTerrassa, Terrassa, Spain

2 Stroke Pharmacogenomics and Genetics, Sant Pau Research Institute, Barcelona, Spain

3 Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain

4 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

5 Neurovascular Research Laboratory, Vall d'Hebron Institute of Research, Universitat Autònoma de Barcelona, Barcelona, Spain

6 Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Spain

7 Cardiovascular Epidemiology and Genetics Research Group, Hospital del Mar Medical Research Institute, Universitat Pompeu Fabra, Barcelona, Spain

8 Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Spain

9 Institucio Catalana de Recerca i Estudis Avançats, Barcelona, Spain

10 Centre for Biomedicine, Manchester Metropolitan University, Manchester, UK

* These authors contributed equally to this work

Correspondence to:

Cristina Gallego-Fabrega,email: cristina.gallego.fabrega@gmail.com
Jerzy Krupinski,email: jkrupinski@mutuaterrassa.es
Israel Fernandez-Cadenas,email: israelcadenas@yahoo.es

Keywords: atherosclerotic plaque; epigenetics; DNA methylation; matrix metalloproteinases

Received: October 09, 2019     Accepted: January 13, 2020     Published: March 10, 2020


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.

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