Genetic polymorphisms associated with thrombotic disorders in the Japanese population

Genetic factors in combination with a number of environmental risk factors are involved in a predisposition to thrombotic disorders. Coronary artery disease (CAD) and ischemic cerebrovascular disease are typical human attributes that have a complex multifactorial etiology. There has been an increased awareness of the contribution of inherited factors for multifactorial disorders like thrombosis since the discovery of two prothrombotic mutations, the factor V Leiden and the prothrombin G20210A mutations, prevalent in Caucasian populations. Elevated plasma levels of homocysteine also constitute a risk factor for venous and arterial thrombosis. Thrombophilia is now thought to be common, not limited to rare conditions such as congenital deficiencies of the physiologic coagulation inhibitors.

It has long been thought that Japan has a lower incidence of thrombotic diseases, although there are only small differences in the prevalence of antithrombin, protein C, or protein S deficiencies. There are, however, critical differences in the prevalence of common polymorphisms relevant to thrombosis. The factor V Leiden and prothrombin mutations are absent in the Japanese, and a polymorphism of a platelet integrin, the glycoprotein IIIa 33Leu/Pro, which has a controversial relationship with arterial thrombosis in Caucasian populations, is very rare in Japan. Also, allele frequencies of some clinically relevant factors are different, including platelets and blood coagulation factors. Thus, a separate study is needed for each population with a distinct ethnic background.

In a number of allelic association studies involving patients with CAD, ischaemic stroke, peripheral artery disease, and vascular complications of diabetes, we found that the effect of genetic factors varied significantly depending on the characteristics of the cases and controls selected. A certain combination of multiple genetic risk factors was found to greatly increase the risk of stroke, particularly in young subjects.

Many genes are involved in determining the inter-individual variation in traits that define the onset and progression of disease, as well as the response to treatment. No single gene is expected to have a major impact on the determination of the risk of thrombosis. The ultimate goal of the clinical appreciation of polymorphic markers is to identify subgroups of individuals in which the disease can be best prevented, or who respond best to interventions.