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Published on: April 1, 2019
Association of MMP-8 promoter gene polymorphisms with carotid atherosclerosis: preliminary study
Tamara Djurić1, Aleksandra Stanković, Igor Končar
1VINČA Institute of Nuclear Sciences, Laboratory for Radiobiology and Molecular Genetics, University of Belgrade, Belgrade, Serbia. tamariska@vinca.rs
Objective:
Matrix metalloproteinases (MMPs) are involved in the remodeling of the extracellular matrix in the arterial wall. Collagen I is associated with vascular smooth muscle cell (VSMC) migration and monocyte differentiation. MMP-8 is expressed in atherosclerotic plaque and preferentially cleaves collagen type I. The aim of this study was to investigate the associations of two MMP-8 promoter polymorphisms, rs11225395 (-799C/T) and rs1320632 (-381 A/G), with carotid plaque occurrence, and the influence of these polymorphisms on MMP-8 mRNA expression in plaque tissue.
Methods:
The study included a total of 766 participants: 277 controls and 489 patients with carotid atherosclerosis undergoing endarterectomy. The two investigated polymorphisms were genotyped by PCR-RFLP. The gene expression analysis was performed by real-time PCR.
Results:
In females only, a significantly higher frequency of the -381G allele was found in patients with carotid atherosclerosis compared to controls (OR, 1.7; 95% CI 1.1-2.9; p = 0.001). Significant up-regulation of MMP-8 gene expression was observed in patients carrying the -381G allele compared to those with the AA genotype (mean factor, 3.54; S.E. range, 0.643-19.551; p = 0.007). Carotid plaque tissue of the haplotype G(-381)T(-799) showed a significantly higher mRNA level compared with the reference A(-381)C(-799) haplotype (p = 0.003).
Conclusion:
Our preliminary results indicate that MMP-8 -381A/G and -799C/T gene polymorphisms could be risk factors for carotid atherosclerosis. Further validation and functional studies are needed to establish the potential regulatory role of these polymorphisms and their impact on susceptibility to carotid atherosclerosis.
Insights
Genetic variations in the MMP-8 gene, specifically the -381A/G and -799C/T promoter polymorphisms, are associated with increased risk of carotid atherosclerosis in females. These polymorphisms also influence MMP-8 gene expression in plaque tissue.
Area of Science:
- Cardiovascular Genetics
- Molecular Biology
- Atherosclerosis Research
Background:
- Matrix metalloproteinases (MMPs) play a role in arterial wall remodeling.
- MMP-8 preferentially cleaves collagen type I, a component linked to vascular smooth muscle cell migration and monocyte differentiation.
- MMP-8 is present in atherosclerotic plaques.
Purpose of the Study:
- To investigate the association of two MMP-8 promoter polymorphisms (rs11225395 and rs1320632) with carotid plaque occurrence.
- To determine the influence of these polymorphisms on MMP-8 mRNA expression in carotid plaque tissue.
Main Methods:
- Genotyping of MMP-8 promoter polymorphisms rs11225395 (-799C/T) and rs1320632 (-381 A/G) using PCR-RFLP in 766 participants (277 controls, 489 patients).
- Gene expression analysis of MMP-8 mRNA in plaque tissue using real-time PCR.
Main Results:
- In females, the -381G allele of MMP-8 was significantly more frequent in carotid atherosclerosis patients (OR, 1.7; p = 0.001).
- MMP-8 gene expression was significantly up-regulated in patients with the -381G allele (mean factor, 3.54; p = 0.007).
- The G(-381)T(-799) haplotype showed significantly higher MMP-8 mRNA levels compared to the A(-381)C(-799) haplotype (p = 0.003).
Conclusions:
- MMP-8 -381A/G and -799C/T gene polymorphisms may represent risk factors for carotid atherosclerosis.
- Further studies are required to elucidate the regulatory role of these polymorphisms in atherosclerosis susceptibility.
