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Genetic background of acute coronary syndromes
European Journal of Internal Medicine 17 (2006) 157 – 162 www.elsevier.com/locate/ejim
Review article
Genetic background of acute coronary syndromes Jozefa Dabek, Andrzej Kulach *, Zbigniew Gasior Department of Cardiology, Medical University of Silesia, Ziolowa 47, PL-40-635 Katowice, Poland Received 4 April 2005; received in revised form 22 September 2005; accepted 17 November 2005
Abstract Acute coronary syndromes (ACS) are one of the major causes of mortality nowadays. Although much is known about factors involved in atherogenesis and acute coronary events, there are still many cases in which a lack of classical risk factors, together with family history, suggests the presence of an unrevealed genetic predisposition and molecular mechanisms. This paper reviews genetic predisposition to ACS. It also indicates which genes are linked to the processes of destabilization and rupture of atherosclerotic plaque and thus may be potential targets for more effective prophylaxis and treatment. D 2006 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. Keywords: Acute coronary syndrome; Myocardial infarction; Unstable angina; Gene polymorphism; Gene expression
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gene polymorphisms and the risk of ACS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Polymorphisms of genes regulating lipid metabolism and the risk of ACS . . . . . . . . . . . . . . . 2.2. Gene polymorphisms of inflammatory factors and the risk of ACS . . . . . . . . . . . . . . . . . . . 2.3. Gene polymorphisms of endothelial factors and matrix components and the risk of ACS . . . . . . . 2.4. Gene polymorphisms of coagulatory and fibrinolytic factors and the risk of ACS . . . . . . . . . . . 3. Research on transcriptional activity of proinflammatory genes in ACS . . . . . . . . . . . . . . . . . . . . 3.1. Gene expression of proinflammatory factors in PBMC in ACS . . . . . . . . . . . . . . . . . . . . . 3.2. Gene expression of proinflammatory factors in atherosclerotic plaque in ACS . . . . . . . . . . . . . 3.3. Gene expression of proinflammatory factors in endocardium and myocardium in ACS . . . . . . . . 3.4. Microarray analysis—a new approach in medical genetics. How will it change our understanding cardiovascular pathology? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Genetic tests in cardiology—ethical concerns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction
* Corresponding author. Tel./fax: +48 32 252 74 07. E-mail address: [email protected] (A. Kulach).
Due to a marked reduction in infectious diseases and to advances in surgery and pharmacotherapy, medicine in the 20th century managed to almost double the average human life span. The leading cause of mortality among adults worldwide became vascular diseases, including cerebrovas-
0953-6205/$ - see front matter D 2006 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2005.11.006
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cular and cardiovascular disease and their major complications: stroke and acute coronary syndromes (ACS). Therefore, it is not surprising that medical research is now focused on the mechanisms leading to these pathologies, as well as on prevention and potential molecular targets in treatment. The direct cause of ACS is the formation of a thrombus, resulting from the rupture of an unstable atherosclerotic plaque. Although numerous risk factors for atherogenesis and ACS are known, a large population still exists for whom a lack of classical risk factors does not allow the start of early prevention and optimized treatment. A more detailed investigation of molecular mechanisms in acute atherothrombosis may lead to a better understanding of its pathophysiology and, in the future, more effective prophylaxis and treatment of acute cardiac events. The purpose of this paper is to review the most important genetic risk factors of ACS, as well as to describe the genes whose transcriptional activity is markedly elevated in coronary events and whose products are markers of ACS. These are likely to be linked to its pathophysiology and are thus potential targets for prophylaxis and therapy.
2. Gene polymorphisms and the risk of ACS The presence of sequence variance in a particular genomic locus is called gene polymorphism. Even a minimal alteration in the base sequence of a gene can significantly change the activity of its product. Such modification, in particular circumstances, can either lead to some pathological processes or protect against them. One such example is the effect of variance of genes encoding major histocompatibility complex on the susceptibility to autoimmune diseases. Liu et al., studying the relationship between HLA-DQA1 polymorphism and susceptibility to idiopathic dilated cardiomyopathy (IDC), reported that the *0501 allele of HLA-DQA1 confers susceptibility to IDC, while the *0201 allele protects against it [1]. Therefore, the evaluation of variations of genes involved in the pathogenesis of a particular disease may be useful both in prognostics and prophylaxis. Arterial hypertension is the model pathology in which the role of gene polymorphisms has been very well evaluated. The best known examples are the polymorphisms of genes encoding angiotensinogen (ATG), angiotensinconverting enzyme (ACE), angiotensin receptor type 1 (AT1R) and aldosterone synthase (CYP11B2) [2]. Many gene variants involved in lipid parameter disorders are also well known. As the pathogenesis of ACS involves numerous endothelial, inflammatory, coagulatory and fibrinolytic factors, one might expect gene polymorphisms of these factors to be associated with the risk of myocardial infarction (MI) or unstable angina (UA).
2.1. Polymorphisms of genes regulating lipid metabolism and the risk of ACS The influence of polymorphisms of genes regulating lipid metabolism (apolipoproteins, receptors and enzymes) on the severity of lipid disorders and atherosclerosis is well documented. The variants of the apolipoprotein E (apoE) gene were the most often evaluated gene polymorphism in the 1990s. There are three alleles of apoE in the population: E2, E3 and E4. The most common genotype is the homozygote E3E3. The minimal difference in amino acid sequence is responsible for the markedly increased affinity of E2 and decreased affinity of apoE4 for the lipoprotein receptor. E2E2 homozygotes (1% of population) manifest primary hyperlipoproteinemia type 3, while E4E4 homozygotes (3% of population) present polygenic hypercholesterolemia. The polymorphism of apoE has been proven to correlate with lipid metabolism disturbances and with coronary artery stenosis. Also, a correlation of apoE gene variance with the risk of ACS has been reported. The presence of the E4 allele is associated with a higher risk of ACS [3 –5], while the E3 allele protects against ACS [3]. Studies of the role of gene polymorphisms of other apolipoproteins in ACS have not revealed such clear influences. Enzymes involved in lipid metabolism have been another target of genetic research in ACS. Some forms of lipoprotein lipase (LPL) are documented to cause predispositions for particular lipid metabolism disturbances. To determine whether LPL gene variants influence susceptibility to MI, Yang et al. studied single nucleotide polymorphisms (SNPs) of the LPL gene. The only finding was a small protective effect of the X447 mutant allele on the risk of ACS [6]. Also, some variants of cholesterol-ester transferring protein (CETP) seem to have a protective effect [7]. 2.2. Gene polymorphisms of inflammatory factors and the risk of ACS Since atherosclerosis and its complications have proven to be a continuous inflammatory process, the question has arisen of genetic susceptibility to plaque development and rupture. Interleukins 1h and 6 are well-known proinflammatory and prothrombotic cytokines participating in the pathology of ACS. Recent studies have revealed that gene polymorphisms of the promoter regions of IL-1h and IL-6 may at least partly support the concept of genetically determined variations in the intensity of inflammatory reactions in patients with ACS. The presence of allele G of the 174G/C IL-6 polymorphism was reported to be correlated with a markedly increased risk of ACS [5]. Similarly, the presence of allele C of the 511C/T IL-1h polymorphism was found to be associated with an elevated risk of cardiac events in elderly men [5], but also seems to be an indicator of increased cardiovascular and cerebrovas-
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cular risk at a young age [8]. Studies on gene variants of the other cytokines participating in atherogenesis and ACS, such as transforming growth factor h (TGFh) and tumor necrosis factor a (TNFa), did not reveal any specific findings. Apart from humoral mediators, cellular interactions and membrane receptors play a key role in the inflammatory process. Ameziane et al. reported a protective effect of the 299Gly isoform of the TLR4 receptor [9]. Humoral and cellular interactions eventually lead to secretion and activation of extracellular, matrix-degrading enzymes (known as matrix metalloproteinases—MMPs), which are responsible for plaque destabilization and rupture. Variation in genes encoding some of these enzymes (e.g., allele 1G of the MMP-1 gene and allele 5A of the MMP-3 gene) may be considered another genetic risk factor for ACS [10,11]. 2.3. Gene polymorphisms of endothelial factors and matrix components and the risk of ACS For many years, blood vessels had been considered to be a simple blood-supplying system, regulated by systemic and local vasoactive factors. However, recent studies on endothelium have now changed this point of view. Endothelium is one of the most active tissues within the body and it participates in almost all processes in the physiology and pathology of the cardiovascular system. Besides the secretion of vasoactive factors, it takes part in coagulation, fibrinolysis, immunological and inflammatory processes, and angiogenesis. Sequence variance in genes encoding endothelial mediators may lead to different reactions of endothelium in these processes. As mentioned above, polymorphisms of genes encoding the renin – angiotensin system that lead to a predisposition to arterial hypertension are quite well defined. The DD genotype of ACE, besides its known relation with impaired vasodilation, has also been proven to increase the risk of ACS [12]. The presence of allele D in the population is not, however, correlated with the intensity of coronary artery disease, which suggests that the participation of a particular form of ACE in ACS is due to impaired regulation of vascular tension rather than atherogenesis promotion. Nitric oxide (NO) is another major product of endothelium that regulates vascular tone. It is produced by at least three forms of nitric oxide synthase (NOS). The gene variants of eNOS – the constitutive NOS expressed in endothelium – may lead to differences in the activity of this enzyme. Although the reports on the role of eNOS gene polymorphisms in ACS are contradictory, the latest data provided by Fatini et al. proved that the 4a4a genotype causes a predisposition to ACS (OR 2.5) and particularly to MI (OR 3.6) [13]. Plaque stability is dependent on the balance between the intensity of inflammation and endothelial dysfunction, on the one hand, and the stability of the matrix, on the other. Some variants of collagen type III result in a higher susceptibility of this protein to degrading factors and may
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influence the effect of GPIIb/IIIa antagonist treatment as well [14]. 2.4. Gene polymorphisms of coagulatory and fibrinolytic factors and the risk of ACS The direct cause of ACS is the formation of an arteryoccluding thrombus that is provoked by the rupture of an atherosclerotic plaque. Since the formation of the clot is dependent on multiple factors regulating coagulation, fibrinolysis and platelet aggregation, various forms of the genes encoding these factors may lead to increased susceptibility to ACS. The PIA2 variant of GPIIb/IIIa was documented to double the risk of ACS [15 – 17]. Its presence is also correlated with impaired efficiency of anti-platelet treatment [18]. Also, polymorphisms 807C/T and 3550C/T of another platelet receptor– GPIa –seem to increase the risk of ACS [16,19]. While the studies on gene variance of coagulation factors are contradictory, the presence of the 20210A polymorphism of prothrombin clearly represents another genetic risk factor for acute thrombosis in ACS, both with and without other coexisting risk factors [4,20]. Among the various other procoagulatory or antifibrinolytic factors, the presence of the 603G polymorphism of tissue factor [21], allele 4G of PAI-1 [22], the AA genotype of PAI-2 [23] and 402A allele of factor VII [24] may provide prognostic value in ACS. On the other hand, some forms of the other factors – such as 323A2 promoter polymorphism of gene encoding factor VII – may protect against ACS [24]. Our contemporary understanding of the pathomechanism of ACS is, despite marked progress, still unsatisfactory and does not allow the probability of a coronary event to be predicted or its course to be foreseen. The gene polymorphisms are one of the reasons for this difference between individuals. As discussed, some variants can increase the risk while others may be protective. The ability to screen patients for a certain set of gene variants could be helpful in risk evaluation and in assessment of their prognosis and their likely reactions to particular forms of treatment.
3. Research on transcriptional activity of proinflammatory genes in ACS The expression of genes lies at the base of all physiological and pathological processes. Research on gene transcriptional activity in ACS focuses on the expression of certain proinflammatory genes in monocytes, peripheral blood mononuclear cells (PBMC), atherosclerotic plaques (obtained during atherectomy or from animal models) and endocardium and myocardium (obtained during cardiac surgery or from animal models). The transcriptional activities of these genes provide a source of information about their role in the pathology of ACS, as well as in the development of early and late vascular and myocardial remodeling leading to post-infarction heart failure.
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3.1. Gene expression of proinflammatory factors in PBMC in ACS Since macrophages are important components of atherosclerotic plaque and are recruited from peripheral blood cells, the activation of monocytes may, at least partly, reflect the processes taking place in the plaque. Such a presumption is the basis for experiments in which monocytes or PBMCs are used to assess the intensity of inflammation in atherosclerotic plaque. The transcriptional activity of genes encoding such classical proinflammatory cytokines as interleukin 1h (IL1h), interleukin 6 (IL-6) and tumor necrosis factor a (TNFa) have been frequently reported in recent years. Akatsu et al. showed that mRNA expression of TNFa and TACE (TNF converting enzyme) is markedly increased in MI and is proportional to the clinical disturbances [25]. Also, gene expression of TRAIL (TNF-related apoptosis-inducing ligand), another necrotic factor in the TNF family, increases in MI, taking part in apoptosis of myocytes [26]. Searching for the source of monocyte activation, Liuzzo et al. showed that the profile of gene expression in monocytes indicates that they are, at least partly, stimulated by interferon g (IFNg). This indicates the participation of T lymphocytes in the pathogenesis of ACS [27]. In recent years, the strategy of research on gene expression has turned from the assessment of single gene expression to gene expression profiling: the evaluation of the activity of a group of functionally linked genes. The study of Wettinger et al. was one of the first assessing the profile of 35 proinflammatory genes in MI and almost all of the assessed genes revealed increased expression [28]. 3.2. Gene expression of proinflammatory factors in atherosclerotic plaque in ACS While the studies evaluating proinflammatory gene expression in monocytes or PBMCs have obvious limitations, they still remain the most common ones because of the simplicity of their method and the accessibility of the material needed. There are, however, some reports on proinflammatory gene expression in atherosclerotic plaque in patients with ACS. Ishibashi et al. reported that gene expression of IL-1h, IL-6, TGFh, ICAM-1 and VCAM-1 is markedly elevated in plaques obtained from patients with unstable angina compared to those with stable angina [29]. However, because of the small number of participants, the results are rather preliminary. A larger investigation on inflammatory gene expression in the atherosclerotic plaque is desirable. 3.3. Gene expression of proinflammatory factors in endocardium and myocardium in ACS In contrast, the level of proinflammatory gene expression in myocardium appears to have a different significance. While elevated levels in monocytes, endothelium and atherosclerotic plaque reflect the inflammatory process
leading to ACS and the development of acute events, the variation of proinflammatory gene expression in myocardium is more likely to reflect different phases of myocardial injury and remodeling. The main source of data on such gene expression in myocardium is animal models. It was observed that, after coronary artery occlusion, transcriptional activity of genes encoding IL-1h and IL-6 increases 50-fold in the acute phase and normalizes after reperfusion [30]. If the myocardium is not reperfused, gene expression rises again after several days [31]. Similar data were collected during human studies in which the expression of IL-1h, IL-6, TNFa, MCP-1, IFNg and iNOS genes were assessed in endocardium in UA, SA and control patients (with UA/SA samples collected during by-pass grafting and with valve replacement patients as the control group). The level of transcriptional activity of the evaluated cytokines was increased sixfold in patients with ACS [32]. 3.4. Microarray analysis—a new approach in medical genetics. How will it change our understanding of cardiovascular pathology? Microarrays are novel, high-throughput genetic tools, based on microhybridization, that allow the study of the expression of thousands of genes in one sample simultaneously. While the analysis of such an enormous number of genes seems to be extremely difficult, it makes it possible to find new links between various genes and may lead to the identification of a unique set of genes associated with a specific disorder. Such subsets can be used to develop microarrays dedicated to a particular disease. In clinical practice, microarrays are currently most widely applied in oncology. Microchips are used for screening, prognostics and the monitoring of treatment. Recently, microarrays have been applied to the investigation of coronary artery disease, including ACS, chronic heart failure and more, to study changes in gene expression profiles in different stages of disease and between diseased healthy subjects [33,34]. The genetic background of ACS has also been evaluated using microarrays, both in animals [35] and in humans [36]. Microarrays in ACS provide insight into molecular bases and dynamics of such processes as apoptosis, angiogenesis or inflammation and may, in the future, contribute to the development of new diagnostic markers and therapeutic options. 3.5. Genetic tests in cardiology—ethical concerns Since genetic tools have been applied in medical practice, they have always raised discussion regarding ethical, legal and social implications (ELSI). Genetic tests for susceptibility to cardiovascular diseases, including ACS, will certainly raise such concerns. The identification of a mutation or polymorphism predisposing to ACS, even if it does not allow for direct treatment, provides valuable
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information that leads to earlier and more aggressive prophylaxis. Moreover, such a finding may point out the need to perform screening tests in relatives. On the other hand, such information must be kept strictly confidential; access to it (and the chance to take advantage of it) by a third party (e.g., insurance company, employer, etc.) should be forbidden. It is also worth mentioning that genetic tests test for susceptibility to a particular disease, not to the disease itself. Often, many concomitant factors must exist before the disease develops.
4. Conclusions The search for markers of genetic susceptibility to ACS is being accomplished in several different ways. Very large studies based on genome-wide linkage analysis are being performed in families with a history of early onset of ACS in order to find new loci that could be responsible for an increased risk of coronary events (Harrap et al., GENECARD) [37,38]. Such studies on gene polymorphisms will hopefully lead to more precise risk stratification, allowing early prophylaxis as well as better predictions of prognosis and reactions to treatment. In addition, the growing number of studies (including gene expression profiling using microarrays) on the transcriptional activity of genes involved in plaque destabilization and rupture provide new insights into our understanding of ACS. This should lead to the development of new therapeutic options for plaque stabilization by the inhibition of inflammatory genes and the promotion of protective factors. Some drugs acting through these mechanisms are already known: the pleiotropic effects of statins support their strong role in the treatment of ACS. Also, data supporting the important anti-inflammatory actions of fibrates –artificial PPARa activators –continue to be gathered. Similarly, some promising data regarding PPARg agonists in ACS have recently appeared [39]. These results, however, raise further questions that will challenge genetics and pharmacology.
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Review article
Genetic background of acute coronary syndromes Jozefa Dabek, Andrzej Kulach *, Zbigniew Gasior Department of Cardiology, Medical University of Silesia, Ziolowa 47, PL-40-635 Katowice, Poland Received 4 April 2005; received in revised form 22 September 2005; accepted 17 November 2005
Abstract Acute coronary syndromes (ACS) are one of the major causes of mortality nowadays. Although much is known about factors involved in atherogenesis and acute coronary events, there are still many cases in which a lack of classical risk factors, together with family history, suggests the presence of an unrevealed genetic predisposition and molecular mechanisms. This paper reviews genetic predisposition to ACS. It also indicates which genes are linked to the processes of destabilization and rupture of atherosclerotic plaque and thus may be potential targets for more effective prophylaxis and treatment. D 2006 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. Keywords: Acute coronary syndrome; Myocardial infarction; Unstable angina; Gene polymorphism; Gene expression
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gene polymorphisms and the risk of ACS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Polymorphisms of genes regulating lipid metabolism and the risk of ACS . . . . . . . . . . . . . . . 2.2. Gene polymorphisms of inflammatory factors and the risk of ACS . . . . . . . . . . . . . . . . . . . 2.3. Gene polymorphisms of endothelial factors and matrix components and the risk of ACS . . . . . . . 2.4. Gene polymorphisms of coagulatory and fibrinolytic factors and the risk of ACS . . . . . . . . . . . 3. Research on transcriptional activity of proinflammatory genes in ACS . . . . . . . . . . . . . . . . . . . . 3.1. Gene expression of proinflammatory factors in PBMC in ACS . . . . . . . . . . . . . . . . . . . . . 3.2. Gene expression of proinflammatory factors in atherosclerotic plaque in ACS . . . . . . . . . . . . . 3.3. Gene expression of proinflammatory factors in endocardium and myocardium in ACS . . . . . . . . 3.4. Microarray analysis—a new approach in medical genetics. How will it change our understanding cardiovascular pathology? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Genetic tests in cardiology—ethical concerns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction
* Corresponding author. Tel./fax: +48 32 252 74 07. E-mail address: [email protected] (A. Kulach).
Due to a marked reduction in infectious diseases and to advances in surgery and pharmacotherapy, medicine in the 20th century managed to almost double the average human life span. The leading cause of mortality among adults worldwide became vascular diseases, including cerebrovas-
0953-6205/$ - see front matter D 2006 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2005.11.006
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cular and cardiovascular disease and their major complications: stroke and acute coronary syndromes (ACS). Therefore, it is not surprising that medical research is now focused on the mechanisms leading to these pathologies, as well as on prevention and potential molecular targets in treatment. The direct cause of ACS is the formation of a thrombus, resulting from the rupture of an unstable atherosclerotic plaque. Although numerous risk factors for atherogenesis and ACS are known, a large population still exists for whom a lack of classical risk factors does not allow the start of early prevention and optimized treatment. A more detailed investigation of molecular mechanisms in acute atherothrombosis may lead to a better understanding of its pathophysiology and, in the future, more effective prophylaxis and treatment of acute cardiac events. The purpose of this paper is to review the most important genetic risk factors of ACS, as well as to describe the genes whose transcriptional activity is markedly elevated in coronary events and whose products are markers of ACS. These are likely to be linked to its pathophysiology and are thus potential targets for prophylaxis and therapy.
2. Gene polymorphisms and the risk of ACS The presence of sequence variance in a particular genomic locus is called gene polymorphism. Even a minimal alteration in the base sequence of a gene can significantly change the activity of its product. Such modification, in particular circumstances, can either lead to some pathological processes or protect against them. One such example is the effect of variance of genes encoding major histocompatibility complex on the susceptibility to autoimmune diseases. Liu et al., studying the relationship between HLA-DQA1 polymorphism and susceptibility to idiopathic dilated cardiomyopathy (IDC), reported that the *0501 allele of HLA-DQA1 confers susceptibility to IDC, while the *0201 allele protects against it [1]. Therefore, the evaluation of variations of genes involved in the pathogenesis of a particular disease may be useful both in prognostics and prophylaxis. Arterial hypertension is the model pathology in which the role of gene polymorphisms has been very well evaluated. The best known examples are the polymorphisms of genes encoding angiotensinogen (ATG), angiotensinconverting enzyme (ACE), angiotensin receptor type 1 (AT1R) and aldosterone synthase (CYP11B2) [2]. Many gene variants involved in lipid parameter disorders are also well known. As the pathogenesis of ACS involves numerous endothelial, inflammatory, coagulatory and fibrinolytic factors, one might expect gene polymorphisms of these factors to be associated with the risk of myocardial infarction (MI) or unstable angina (UA).
2.1. Polymorphisms of genes regulating lipid metabolism and the risk of ACS The influence of polymorphisms of genes regulating lipid metabolism (apolipoproteins, receptors and enzymes) on the severity of lipid disorders and atherosclerosis is well documented. The variants of the apolipoprotein E (apoE) gene were the most often evaluated gene polymorphism in the 1990s. There are three alleles of apoE in the population: E2, E3 and E4. The most common genotype is the homozygote E3E3. The minimal difference in amino acid sequence is responsible for the markedly increased affinity of E2 and decreased affinity of apoE4 for the lipoprotein receptor. E2E2 homozygotes (1% of population) manifest primary hyperlipoproteinemia type 3, while E4E4 homozygotes (3% of population) present polygenic hypercholesterolemia. The polymorphism of apoE has been proven to correlate with lipid metabolism disturbances and with coronary artery stenosis. Also, a correlation of apoE gene variance with the risk of ACS has been reported. The presence of the E4 allele is associated with a higher risk of ACS [3 –5], while the E3 allele protects against ACS [3]. Studies of the role of gene polymorphisms of other apolipoproteins in ACS have not revealed such clear influences. Enzymes involved in lipid metabolism have been another target of genetic research in ACS. Some forms of lipoprotein lipase (LPL) are documented to cause predispositions for particular lipid metabolism disturbances. To determine whether LPL gene variants influence susceptibility to MI, Yang et al. studied single nucleotide polymorphisms (SNPs) of the LPL gene. The only finding was a small protective effect of the X447 mutant allele on the risk of ACS [6]. Also, some variants of cholesterol-ester transferring protein (CETP) seem to have a protective effect [7]. 2.2. Gene polymorphisms of inflammatory factors and the risk of ACS Since atherosclerosis and its complications have proven to be a continuous inflammatory process, the question has arisen of genetic susceptibility to plaque development and rupture. Interleukins 1h and 6 are well-known proinflammatory and prothrombotic cytokines participating in the pathology of ACS. Recent studies have revealed that gene polymorphisms of the promoter regions of IL-1h and IL-6 may at least partly support the concept of genetically determined variations in the intensity of inflammatory reactions in patients with ACS. The presence of allele G of the 174G/C IL-6 polymorphism was reported to be correlated with a markedly increased risk of ACS [5]. Similarly, the presence of allele C of the 511C/T IL-1h polymorphism was found to be associated with an elevated risk of cardiac events in elderly men [5], but also seems to be an indicator of increased cardiovascular and cerebrovas-
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cular risk at a young age [8]. Studies on gene variants of the other cytokines participating in atherogenesis and ACS, such as transforming growth factor h (TGFh) and tumor necrosis factor a (TNFa), did not reveal any specific findings. Apart from humoral mediators, cellular interactions and membrane receptors play a key role in the inflammatory process. Ameziane et al. reported a protective effect of the 299Gly isoform of the TLR4 receptor [9]. Humoral and cellular interactions eventually lead to secretion and activation of extracellular, matrix-degrading enzymes (known as matrix metalloproteinases—MMPs), which are responsible for plaque destabilization and rupture. Variation in genes encoding some of these enzymes (e.g., allele 1G of the MMP-1 gene and allele 5A of the MMP-3 gene) may be considered another genetic risk factor for ACS [10,11]. 2.3. Gene polymorphisms of endothelial factors and matrix components and the risk of ACS For many years, blood vessels had been considered to be a simple blood-supplying system, regulated by systemic and local vasoactive factors. However, recent studies on endothelium have now changed this point of view. Endothelium is one of the most active tissues within the body and it participates in almost all processes in the physiology and pathology of the cardiovascular system. Besides the secretion of vasoactive factors, it takes part in coagulation, fibrinolysis, immunological and inflammatory processes, and angiogenesis. Sequence variance in genes encoding endothelial mediators may lead to different reactions of endothelium in these processes. As mentioned above, polymorphisms of genes encoding the renin – angiotensin system that lead to a predisposition to arterial hypertension are quite well defined. The DD genotype of ACE, besides its known relation with impaired vasodilation, has also been proven to increase the risk of ACS [12]. The presence of allele D in the population is not, however, correlated with the intensity of coronary artery disease, which suggests that the participation of a particular form of ACE in ACS is due to impaired regulation of vascular tension rather than atherogenesis promotion. Nitric oxide (NO) is another major product of endothelium that regulates vascular tone. It is produced by at least three forms of nitric oxide synthase (NOS). The gene variants of eNOS – the constitutive NOS expressed in endothelium – may lead to differences in the activity of this enzyme. Although the reports on the role of eNOS gene polymorphisms in ACS are contradictory, the latest data provided by Fatini et al. proved that the 4a4a genotype causes a predisposition to ACS (OR 2.5) and particularly to MI (OR 3.6) [13]. Plaque stability is dependent on the balance between the intensity of inflammation and endothelial dysfunction, on the one hand, and the stability of the matrix, on the other. Some variants of collagen type III result in a higher susceptibility of this protein to degrading factors and may
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influence the effect of GPIIb/IIIa antagonist treatment as well [14]. 2.4. Gene polymorphisms of coagulatory and fibrinolytic factors and the risk of ACS The direct cause of ACS is the formation of an arteryoccluding thrombus that is provoked by the rupture of an atherosclerotic plaque. Since the formation of the clot is dependent on multiple factors regulating coagulation, fibrinolysis and platelet aggregation, various forms of the genes encoding these factors may lead to increased susceptibility to ACS. The PIA2 variant of GPIIb/IIIa was documented to double the risk of ACS [15 – 17]. Its presence is also correlated with impaired efficiency of anti-platelet treatment [18]. Also, polymorphisms 807C/T and 3550C/T of another platelet receptor– GPIa –seem to increase the risk of ACS [16,19]. While the studies on gene variance of coagulation factors are contradictory, the presence of the 20210A polymorphism of prothrombin clearly represents another genetic risk factor for acute thrombosis in ACS, both with and without other coexisting risk factors [4,20]. Among the various other procoagulatory or antifibrinolytic factors, the presence of the 603G polymorphism of tissue factor [21], allele 4G of PAI-1 [22], the AA genotype of PAI-2 [23] and 402A allele of factor VII [24] may provide prognostic value in ACS. On the other hand, some forms of the other factors – such as 323A2 promoter polymorphism of gene encoding factor VII – may protect against ACS [24]. Our contemporary understanding of the pathomechanism of ACS is, despite marked progress, still unsatisfactory and does not allow the probability of a coronary event to be predicted or its course to be foreseen. The gene polymorphisms are one of the reasons for this difference between individuals. As discussed, some variants can increase the risk while others may be protective. The ability to screen patients for a certain set of gene variants could be helpful in risk evaluation and in assessment of their prognosis and their likely reactions to particular forms of treatment.
3. Research on transcriptional activity of proinflammatory genes in ACS The expression of genes lies at the base of all physiological and pathological processes. Research on gene transcriptional activity in ACS focuses on the expression of certain proinflammatory genes in monocytes, peripheral blood mononuclear cells (PBMC), atherosclerotic plaques (obtained during atherectomy or from animal models) and endocardium and myocardium (obtained during cardiac surgery or from animal models). The transcriptional activities of these genes provide a source of information about their role in the pathology of ACS, as well as in the development of early and late vascular and myocardial remodeling leading to post-infarction heart failure.
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3.1. Gene expression of proinflammatory factors in PBMC in ACS Since macrophages are important components of atherosclerotic plaque and are recruited from peripheral blood cells, the activation of monocytes may, at least partly, reflect the processes taking place in the plaque. Such a presumption is the basis for experiments in which monocytes or PBMCs are used to assess the intensity of inflammation in atherosclerotic plaque. The transcriptional activity of genes encoding such classical proinflammatory cytokines as interleukin 1h (IL1h), interleukin 6 (IL-6) and tumor necrosis factor a (TNFa) have been frequently reported in recent years. Akatsu et al. showed that mRNA expression of TNFa and TACE (TNF converting enzyme) is markedly increased in MI and is proportional to the clinical disturbances [25]. Also, gene expression of TRAIL (TNF-related apoptosis-inducing ligand), another necrotic factor in the TNF family, increases in MI, taking part in apoptosis of myocytes [26]. Searching for the source of monocyte activation, Liuzzo et al. showed that the profile of gene expression in monocytes indicates that they are, at least partly, stimulated by interferon g (IFNg). This indicates the participation of T lymphocytes in the pathogenesis of ACS [27]. In recent years, the strategy of research on gene expression has turned from the assessment of single gene expression to gene expression profiling: the evaluation of the activity of a group of functionally linked genes. The study of Wettinger et al. was one of the first assessing the profile of 35 proinflammatory genes in MI and almost all of the assessed genes revealed increased expression [28]. 3.2. Gene expression of proinflammatory factors in atherosclerotic plaque in ACS While the studies evaluating proinflammatory gene expression in monocytes or PBMCs have obvious limitations, they still remain the most common ones because of the simplicity of their method and the accessibility of the material needed. There are, however, some reports on proinflammatory gene expression in atherosclerotic plaque in patients with ACS. Ishibashi et al. reported that gene expression of IL-1h, IL-6, TGFh, ICAM-1 and VCAM-1 is markedly elevated in plaques obtained from patients with unstable angina compared to those with stable angina [29]. However, because of the small number of participants, the results are rather preliminary. A larger investigation on inflammatory gene expression in the atherosclerotic plaque is desirable. 3.3. Gene expression of proinflammatory factors in endocardium and myocardium in ACS In contrast, the level of proinflammatory gene expression in myocardium appears to have a different significance. While elevated levels in monocytes, endothelium and atherosclerotic plaque reflect the inflammatory process
leading to ACS and the development of acute events, the variation of proinflammatory gene expression in myocardium is more likely to reflect different phases of myocardial injury and remodeling. The main source of data on such gene expression in myocardium is animal models. It was observed that, after coronary artery occlusion, transcriptional activity of genes encoding IL-1h and IL-6 increases 50-fold in the acute phase and normalizes after reperfusion [30]. If the myocardium is not reperfused, gene expression rises again after several days [31]. Similar data were collected during human studies in which the expression of IL-1h, IL-6, TNFa, MCP-1, IFNg and iNOS genes were assessed in endocardium in UA, SA and control patients (with UA/SA samples collected during by-pass grafting and with valve replacement patients as the control group). The level of transcriptional activity of the evaluated cytokines was increased sixfold in patients with ACS [32]. 3.4. Microarray analysis—a new approach in medical genetics. How will it change our understanding of cardiovascular pathology? Microarrays are novel, high-throughput genetic tools, based on microhybridization, that allow the study of the expression of thousands of genes in one sample simultaneously. While the analysis of such an enormous number of genes seems to be extremely difficult, it makes it possible to find new links between various genes and may lead to the identification of a unique set of genes associated with a specific disorder. Such subsets can be used to develop microarrays dedicated to a particular disease. In clinical practice, microarrays are currently most widely applied in oncology. Microchips are used for screening, prognostics and the monitoring of treatment. Recently, microarrays have been applied to the investigation of coronary artery disease, including ACS, chronic heart failure and more, to study changes in gene expression profiles in different stages of disease and between diseased healthy subjects [33,34]. The genetic background of ACS has also been evaluated using microarrays, both in animals [35] and in humans [36]. Microarrays in ACS provide insight into molecular bases and dynamics of such processes as apoptosis, angiogenesis or inflammation and may, in the future, contribute to the development of new diagnostic markers and therapeutic options. 3.5. Genetic tests in cardiology—ethical concerns Since genetic tools have been applied in medical practice, they have always raised discussion regarding ethical, legal and social implications (ELSI). Genetic tests for susceptibility to cardiovascular diseases, including ACS, will certainly raise such concerns. The identification of a mutation or polymorphism predisposing to ACS, even if it does not allow for direct treatment, provides valuable
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information that leads to earlier and more aggressive prophylaxis. Moreover, such a finding may point out the need to perform screening tests in relatives. On the other hand, such information must be kept strictly confidential; access to it (and the chance to take advantage of it) by a third party (e.g., insurance company, employer, etc.) should be forbidden. It is also worth mentioning that genetic tests test for susceptibility to a particular disease, not to the disease itself. Often, many concomitant factors must exist before the disease develops.
4. Conclusions The search for markers of genetic susceptibility to ACS is being accomplished in several different ways. Very large studies based on genome-wide linkage analysis are being performed in families with a history of early onset of ACS in order to find new loci that could be responsible for an increased risk of coronary events (Harrap et al., GENECARD) [37,38]. Such studies on gene polymorphisms will hopefully lead to more precise risk stratification, allowing early prophylaxis as well as better predictions of prognosis and reactions to treatment. In addition, the growing number of studies (including gene expression profiling using microarrays) on the transcriptional activity of genes involved in plaque destabilization and rupture provide new insights into our understanding of ACS. This should lead to the development of new therapeutic options for plaque stabilization by the inhibition of inflammatory genes and the promotion of protective factors. Some drugs acting through these mechanisms are already known: the pleiotropic effects of statins support their strong role in the treatment of ACS. Also, data supporting the important anti-inflammatory actions of fibrates –artificial PPARa activators –continue to be gathered. Similarly, some promising data regarding PPARg agonists in ACS have recently appeared [39]. These results, however, raise further questions that will challenge genetics and pharmacology.
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