A study of the impacts of expression and genetic variation of matrix metalloproteinases on atherosclerosis

Abstract

In this thesis it was investigated, quantitatively, whether transcript levels of MMPs in carotid atherosclerotic plaques were correlated with histographical features and clinical manifestations of atherosclerosis.  Atherosclerotic plaques removed from patients undergoing carotid endarterectomy were classified histologically using a system proposed by Virmani, and MMP-1, -3, -7, -9 and -12 transcript levels in these tissues were quantified using the technique of real-time reverse-transcripase polymerase chain reaction.  The levels of MMP transcripts varied in different types of atherosclerotic plaque.  They were higher in lesions with a thin fibrous cap (a characteristic of plaques that are prone to rupture, i.e. unstable plaques) that in those with a thick fibrous cap (stable plaques).  Transcript levels were most significantly higher in unstable plaques for MMP-1 (p=0.008).  Also, MMP-1 and MMP-12 transcript levels were significantly higher in plaques from symptomatic patients, particular those with amaurosis fugax, compared to asymptomatic patients (p=0.029 (MMP-1) and p=0.008 (MMP-12)).

To test the hypothesis that variation in MMP genes influences the development of atherosclerosis and the stability of atherosclerotic plaques, common polymorphisms in MMPs -1, -7, -9 and 12 were analysed in a large cohort of Caucasian subjects undergoing coronary angiography.  Genotypes were determined using restriction enzyme digestion of PCR products or tetra primer PCR methods.  The subjects were divided into different groups of patients and genotype frequencies were compared between the groups.  Several MMP polymorphisms were found to contribute to patient-to-patient variability in clinical manifestations of atherosclerosis, and disease severity.  The MMP-9 C-1562T polymorphism was found to be associated with coronary stenosis.  Individuals carrying the T allele had a 1.5 fold higher risk of developing coronary stenosis, compared to those who did not carry the T allele (p=0.03).  There was also a trend towards more extensive coronary atherosclerosis in individuals carrying the T allele.  Haplotype analyses showed that the MMP-9 C-G-C haplotype (-1562C, +279Q and +6C) was associated with a protective effect against atherosclerosis.  Individuals with the C-G-C haplotype had an approximately 70% risk of developing coronary stenosis, compared with those not carrying this haplotype (p=0.01).  Furthermore, the C-G-C haplotype was found to be associated with less extensive coronary atherosclerosis (p=0.04).  The MMP-12 A-82G variant was found to be an independent risk factor for myocardial infarction.  Patients with coronary atherosclerosis who carried the G allele had a 1.5 fold higher risk of suffering from myocardial infarction, compared with those who did not carry this allele (p=0.003).  The G-839A and T-340C MMP-1 promoter polymorphisms were also associated with risk of MI.  Individuals carrying the -839 G allele and those carrying the -340 T allele had an approximately1.5 fold higher risk of MI compared with those not carrying these alleles (p=0.002 and p=0.011, respectively).

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