Genetic polymorphisms and the risk of coronary artery disease

Background: Myocardial infarction involves the three processes of atheroma development, plaque rupture and formation of a thrombus. Proliferation of smooth muscle cells and vasoconstriction are important aspects of atheroma formation and are influenced by the renin-angiotensin system. Angiotensin converting enzyme (ACE) pivotal to this system has recently been shown to be influenced by an insertion/deletion (I/D) polymorphism in the ACE gene. Patients homozygous for the D allele have the highest circulating levels. Inhibition of fibrinolysis through raised levels of plasminogen activator Inhibitor (PAI- 1) has also been shown to be under the control of a PAI-1 promoter single nucleotide insertion/deletion (4G/5G) polymorphism. Patients homozygous for the 4G allele have the highest levels of circulating PAI-1. Aims: The aim of this thesis, was to investigate the role of both polymorphisms in relation to atherothrombosis in subjects with coronary artery disease (CAD). Results: 609 Caucasian patients (420 males 189 females) admitted for angiography for known or suspected coronary artery disease were recruited from two centres. Patients were classified as having no significant coronary artery disease (20%), single (21%), double (21%) and triple vessel disease (38%) on the basis of 50% stenosis. Both the ACE genotype and the PAI-1 genotype were associated with their respective circulating levels (P= 0.0008) and (P = 0.0001) respectively. There was no relationship between the ACE genotype or levels with either the degree of coronary stenosis or a history of MI. In contrast, the 4G/4G genotype was significantly related to a history of myocardial infarction, an association which was stronger in the group with pre-existing significant atheroma. Conclusions: These data suggests that the ACE genotype-activity does not influence the atherothrombotic process, whereas the PAI-1 promoter polymorphism influences the development of myocardial infarction through its effects on thrombus formation in patients with pre-existing atheroma. Conclusions These data suggests that the ACE genotype-activity does not influence the atherothrombotic process, whereas the PAI-1 promoter polymorphism influences the development of myocardial infarction through its effects on thrombus formation in patients with pre-existing atheroma