Haemostasis plays an integral role in arterial thrombotic disease. Identifying risk factors has, however, proved to be surprisingly difficult.68--75 Once established as a risk factor, a genetic polymorphism has the potential to aid selective prophylaxis and therapy of disease. Numerous reports have been published on polymorphisms of coagulation and fibrinolytic factors, of coagulation and fibri-nolytic inhibitory proteins, and of platelet membrane glycoprotein receptors.76--92 Although many studies have shown an association between polymorphisms and disease, the collective outcome of these studies has primarily been inconsistent.
Heart disease, diabetes, and many cancers probably arise from the interaction of acquired and genetic factors. For arterial thrombotic diseases, such as, myocardial infarction and stroke a number of environmental risk factors are well-established, including smoking, diet, dyslipidaemia, hypertension, and impaired glucose metabolism. The role of haemostatic disorders in the development of arterial thrombosis is emerging.68--75 Arterial thrombogenesis results from atherosclerosis and thrombosis, while atherosclerosis is a disease of the vessel wall resulting from chronic changes in vessel wall cellular components, occurring gradually over many years. The thrombotic event is an acute event thought to be triggered by tissue factor interaction with factor Vila and almost certainly influenced by haemostatic factors, such as, fibrinogen, fibrinolytic factors, and platelet activation.86--88 How the atherosclerotic process might be influenced by haemostatic factors is less clear.72,77
Some of the polymorphisms in coagulation and coagulation inhibitor genes studied include polymorphisms; of fibrinogen, factor VII, factor V/prothrombin, factor XIII, thrombomodulin/ endothelial cell protein C receptor, fibrinolytic system genes (PAI-1), platelet glycoprotein receptors (GP IIb/IIIa, GP Ib-IX-V, GP Ia/Iia) and other coagulation proteins.78--92
Knowledge of genetic risk factors may define the pathogenesis of arterial disease and could ultimately help in the rational design of selective therapy. In approaching a large and often contradictory literature, it is helpful to have some basic premises in mind with which to assess the data. For this purpose, two critical premises should be considered. The first is fundamental; for a gene change to have an effect it must be mediated through a phenotype. In studies that report consistent relationships linking polymorphisms, phenotype, and clinical effect there can be some confidence that the genetic variation is influencing disease. In contrast, studies that report only the results ofassociations between polymorphisms and disease should be considered inadequate. This is because any statistically significant association between polymorphism and disease mightwell have arisen for reasons unrelated to the effect of its phenotype. Examples of such confounding factors include play of chance, linkage with another gene locus, and poor study design resulting in bias. The second related premise to be used is whether a polymorphism is making an important contribution to disease and therefore, causing thrombosis.
Adopting the above strategy in analysing the data based on the relation between genotype, phenotype, and clinical outcome reveals that despite extensive investigation, there is still no clear reproducible evidence for the role of any haemostatic polymorphism in arterial thrombosis. This contrasts with the well-defined role of some of the same polymorphisms in VTE.33,35 It is worth considering why this might be. There are fundamental differences between arterial and venous disease, with the dominant role of the vessel wall in the former. It can also be assumed that the haemostatic changes will play a crucial role in the thrombotic complications of arterial disease, mediated through atheromatous plaque rupture, fibrin generation, and platelet activation. It is, however, generally thought that arterial occlusion has a multifactorial aetiology, which conspires to undermine the integrity of the vessel wall and promote thrombosis. Some of these processes, which may involve haemostatic factors, will be influenced by genetic variation. Given the large number of factors, together with the lack of penetrance of disease in families, it is highly unlikely that individual haemostatic polymorphisms will have dominant influences on their own. Consequently, studies that focused only on the prevalence of a specific polymorphism in cohorts of patients (and controls), inevitably failed to show in a reproducible manner that the genetic variation is associated with disease. Apart from their lack of power, small studies are particularly prone to bias. The prevalence of polymorphisms in control groups may be underestimated, resulting in apparent, but spurious increased prevalences in case groups (stratification bias). Poor matching of cases and controls due to racial and population genetic heterogeneity is more likely with small numbers (admixture bias). It is certain that such factors have contributed to an over-representation of published studies reporting positive associations between polymorphisms and disease (publication bias).
A key consideration for future work must be the extent to which classical cardiovascular (acquired and genetically determined) risk factors for disease interact with polymorphisms of the haemostatic system. Gene polymorphisms have existed within populations for thousands of years, while arterial disease has reached epidemic proportions only in the last century. This must have arisen through deleterious gene-environment interactions and suggests that the best means by which the influence of the genetic factor on disease will be reliably detected is by using studies that formally incorporate geneenvironment interactions into their design. In retrospect, it is not surprising that so little progress has been made in this area. Fortunately, some studies had been designed at the outset to study interactions. These studies have produced plausible results of increasing risks of disease with increasing interaction, which fit current concepts of the aetiology of arterial disease. As clinical studies of interaction, however, require very large number of patients/controls, the power of most good studies has nevertheless been low. Consequently, there is an urgent need to address the role of haemostatic polymorphisms with well-designed studies that are larger by at least an order of magnitude. An upward scale change in terms of the number of potential risk alleles under evaluation may also be required, which is now possible with the microarray technologies. Such investigations may identify key combinations of polymorphisms that have low individual risks, but together may influence disease.
The prospect is for genetic screening of asymptomatic individuals, to identify their genetic risk profiles. On the basis of a screening programme, lifestyle advice and individualised pharmacological intervention programmes would be given to reduce future risks of disease. Today, it appears that insufficient progress has been made to justify the inclusion of haemostatic gene polymorphisms within such a population genetic screening programme.
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