Gene polymorphisms of the haemostatic system and the risk of arterial thrombotic disease

Atherosclerosis is a degenerative inflammatory disease of the intima of medium and large arterial vessels (Henderson, 1996; Ross, 1999). This disease, or group of diseases, is a leading cause of morbidity and mortality in western societies. Atherosclerosis may present itself in different manners, to a large extent depending on location and complications, such as myocardial infarction (MI), angina pectoris, cerebral ischaemia and peripheral artery disease. A multitude of factors are known to predispose to atherosclerosis, and these factors are generally referred to as risk factors or risk indicators (Hennekens, 1998). Generally accepted risk factors include cigarette smoking, physical inactivity, inherited or acquired dyslipidaemia, hypertension, diabetes, obesity, metabolic syndrome, menopause, hyperhomocysteinaemia, male gender and a positive family history of arterial disease (Glass & Witztum, 2001; Tegos et al, 2001). This extensive listing serves to illustrate that there is not one cause of atherosclerosis, but that atherosclerosis is a complex or multifactorial disease in which both inherited and acquired factors play a significant role. The notion that genes play an important role in arterial thrombosis may also be inferred from the finding that a familial component is often present in cases presenting with arterial disease (Hamsten, 1996; Friedlander et al, 2001). In most cases, the risk linked to a positive family history cannot be attributed to familial aggregation of `classical' risk factors (Hamsten, 1996). Furthermore, the effect of a positive family history seems to be of particular relevance in patients at (apparently) low risk (Hamsten, 1996). In addition to the risk factors and indicators listed above, the blood coagulation system has also been alleged to determine the onset and outcome of atherosclerosis (Cooper et al, 2000). There are two principal reasons for this presumption. The first reason is that cleavage products from the coagulation system, e.g. thrombin, factor Xa, factor VIIa and activated protein C, may exert proand anti-inflammatory effects on endothelial cells and leucocytes (Esmon et al, 1991). The inflammatory responses of these cells to bloodborne factors are thought to be crucial to the atherosclerotic process (Buja & Willerson, 1994; Libby, 1996; Tracy, 1999). The second reason is that the formation of small blood clots that occlude major arteries, as occurs in, for instance, myocardial infarction or ischaemic stroke, represents the leading complication of atherosclerosis (Fuster et al, 1996; Rentrop, 2000). Subtle interindividual differences in the response of the coagulation system may modify the risk of arterial thrombosis. Thus, the search for haemostatic candidate genes and polymorphisms involved in the predisposition to atherosclerosis and arterial thrombosis represents an important step towards a more comprehensive understanding of the pathogenesis of the disease (Risch, 2000). Indeed, an impressive number of polymorphisms in genes coding for proteins of the haemostatic system have been claimed to influence risk (Lowe, 1997; Marian, 1998; Lane & Grant, 2000; Sykes et al, 2000; Winkelmann & Hager, 2000; Reiner et al, 2001a). Several issues complicate a review of the available data on candidate haemostatic genetic risk factors. The first problem is inherent to the two putative roles of the coagulation system, i.e. modulating the inflammatory response and determining the rate of clot formation, which are not always easily separated in an investigation of patients with atherosclerotic disease. Secondly, sources of data are heterogeneous, and both descriptive and analytical investigations have yielded a myriad of findings, which are often contradictory. Diversity of study design may contribute to the discrepancies, making direct comparisons between studies complicated. Many studies also suffer from a limited sample size, which is frequently too small to confirm or rule out the presence of a relevant epidemiological association between specific polymorphisms and cardiovascular disease. In addition, it is unlikely that specific haemostatic gene variations are, in isolation, very strong risk factors for arterial disease. More probable is the scenario in which haemostatic gene polymorphisms influence atherosclerosis or arterial thrombotic risk by interacting with other established genetic or acquired risk factors. Such interactions may not be apparent in all investigations because of the influence of factors such as sample size, ethnicity (which may also affect the nature and magnitude of gene±gene and gene±environmental interactions), selection and recall bias in case±control studies and clinical end-points. Another relevant point is that many candidate polymorphisms may be in linkage disequilibrium with actual disease-causing polymorphisms (a variation located somewhere in the regulatory or coding region of the same gene or even in another gene). The degree of disequilibrium may vary from population to population, a fact that may also be responsible for some of the discrepancies between studies analysing the same gene variation as a risk factor for arterial thrombosis.