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Published on: September 7, 2017
DNA methylation of MMPs and TIMPs in atherothrombosis process in carotid plaques and blood tissues
Cristina Gallego-Fabrega1,2, Natalia Cullell1,2,3, Carolina Soriano-Tárraga4
1Neurology, Hospital Universitari Mútua de Terrassa/Fundacio Docència i Recerca MutuaTerrassa, Terrassa, Spain.
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.
Insights
DNA methylation patterns in Matrix Metalloproteinases (MMP) and Tissue Inhibitor of Metalloproteinases (TIMP) genes differ between stable and unstable carotid plaques. These DNA methylation changes, particularly in MMP24, are also observed in blood samples from patients with atherothrombotic stroke.
Area of Science:
- Epigenetics
- Cardiovascular Biology
- Genomics
Background:
- Matrix Metalloproteinases (MMP) and Tissue Inhibitor of Metalloproteinases (TIMP) are implicated in atheromatous plaques and ischemic stroke.
- Previous research focused on polymorphisms and serum levels, neglecting DNA methylation patterns of MMP and TIMP genes.
Purpose of the Study:
- To investigate DNA methylation (DNAm) levels of MMP and TIMP gene families in human carotid plaques and blood samples from atherothrombotic stroke patients.
- To identify specific DNAm patterns associated with plaque stability and stroke risk.
Main Methods:
- DNAm status of stable and unstable atherosclerotic carotid plaques from three patients was profiled.
- 415 CpG sites in MMP and TIMP genes were analyzed.
- Associated CpG sites were further analyzed in blood samples from two atherothrombotic stroke cohorts (n=307) using high-density microarrays.
Main Results:
- Three CpG sites showed significant association with unstable plaque portions: cg02969624 (TIMP2) and cg04316754 (MMP24) were hypermethylated, while cg24211657 (TIMP2) was hypomethylated.
- Methylation levels of cg04316754 (MMP24) in blood samples correlated with atherothrombotic risk in both stroke cohorts (p=0.03 and p=1.9 × 10⁻⁰⁴).
Conclusions:
- DNA methylation patterns of MMP24 differ between stable and unstable atherothrombotic carotid plaques.
- Distinct DNA methylation profiles in blood samples differentiate atherothrombotic stroke patients from controls, particularly involving MMP24.
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