TY - JOUR
T1 - DNA methylation of MMPs and TIMPs in atherothrombosis process in carotid plaques and blood tissues
AU - Gallego-Fabrega, Cristina
AU - Cullell, Natalia
AU - Soriano-Tárraga, Carolina
AU - Carrera, Caty
AU - Torres-Aguila, Nuria P
AU - Muiño, Elena
AU - Cárcel-Márquez, Jara
AU - de Moura, Manuel Castro
AU - Fernández-Sanlés, Alba
AU - Esteller, Manel
AU - Elosua, Roberto
AU - Jiménez-Conde, Jordi
AU - Roquer, Jaume
AU - Montaner, Joan
AU - Krupinski, Jerzy
AU - Fernandez-Cadenas, Israel
N1 - Funding: This study was funded by the INVICTUS network, Generacion, Maestro EPIGENESIS, FEDER-ERDF, and BasicMar Regist projects from the Carlos III Health Institute, the AGAUR, the RecerCaixa 2013 and the European Regional Development Fund (ERDF). I. Fernandez is recipient of a research contract from Miguel Servet Program from the Carlos III Health Institute (CPII17/00021). EPIGENESIS project (CarlosIII Institute, Marató TV3 and Fundació MútuaTerrassa).
PY - 2020/3/10
Y1 - 2020/3/10
N2 - 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.
AB - 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.
KW - Atherosclerotic plaque
KW - Epigenetics
KW - DNA methylation
KW - Matrix metalloproteinases
U2 - 10.18632/oncotarget.27469
DO - 10.18632/oncotarget.27469
M3 - Article
C2 - 32206187
SN - 1949-2553
VL - 11
SP - 905
EP - 912
JO - Oncotarget
JF - Oncotarget
IS - 10
ER -