ESTABLISHMENT OF DNA TESTING SYSTEMS FOR THE DIAGNOSES OF GENETIC SUSCEPTIBILITY OF ATHEROSCLEROSIS AND THROMBOSIS

遗传因素和一些环境风险因素共同导致动脉粥样硬化和血栓形成。冠状动脉疾病（CAD）和缺血性脑血管疾病（CVD）是典型的人类属性，具有复杂的多因素病因。本研究的目的是通过一系列涉及CAD、CVD和深静脉血栓形成患者的病例对照研究，阐明与血栓形成相关因素的遗传多态性与疾病表型（即血栓部位和动脉粥样硬化严重程度）之间的关系。我们还旨在建立系统，以全面评估遗传因素对日本人群血栓形成发病机制的贡献，其中等位基因频率已知与高加索人有很大不同。血小板GPIba受体和凝血因子XII多态性与CVD易感性有关。我们还发现CETP和MTHFR的多态性与2型糖尿病的大血管病变有关。此外，因子XII多态性与糖尿病患者腹主动脉钙化有关。本研究的另一个新发现是某些因子（对氧磷酶、同型半胱氨酸、活化凝血因子XII、ANP）的活性或浓度与每个基因内多态性之间的关系。如先前在获得性因素中所示，多种遗传因素的组合被认为对血栓性疾病的发展至关重要。因此，我们开发了一种新的策略来同时分析相关多态性的基因型。我们还建立了在pcr中扩增全血相关DNA片段的方法。临床评价多态性标记的最终目标是确定最能预防疾病发展的个体亚群，或对饮食、行为或药物干预反应最好的个体亚群。为此，多态性不仅需要研究与疾病易感性的关系，还需要研究对治疗的反应性和基因与环境的相互作用。此外，开发新的战略来全面评估日本人特有的风险因素是必要的。少

Genetic factors in combination with a number of environmental risk factors are involved in a predisposition to atherosclerosis and thrombosis. Coronary artery disease (CAD) and ischemic cerebrovascular disease (CVD) are typical human attributes that have a complex multifactorial etiology. The aim of the present study was to clarify the relationship between genetic polymorphisms found in factors relevant to thrombosis and disease phenotypes (i.e., sites of thrombus and severity of atherosclerosis), through a series of case-control studies involving patients with CAD, CVD, and deep vein thrombosis. We also aimed to establish systems to comprehensively evaluate the contribution of genetic factors to the pathogenesis of thrombosis in the Japanese populations, where allele frequencies are known to be quite different than Caucasians.Polymorphisms in platelet GPIba receptor and coagulation factor XII were involved in susceptibility to CVD. We also found that polymorphisms in CETP and MTHFR we … More re associated with macroangiopathy in type 2 diabetes. In addition, factor XII polymorphism was associated with calcification of abdominal aorta in diabetic patients. Another novel finding of this study was the relationships between the activities or concentrations of certain factors (paraoxonase, homocystein, activated coagulation factor XII, ANP) and polymorphisms within each gene.As previously shown in acquired factors, combinations of multiple genetic factors are believed to be crucial for the development of thrombotic disorders. We thus developed a new strategy to simultaneously analyze the genotypes of relevant polymorphisms. We also established methods to amplify relevant DNA fragments from whole blood in PCRs.The ultimate goal of the clinical appreciation of polymorphic markers is to identify subgroups of individuals who are best prevented from developing diseases, or who respond best to dietary, behavioral, or pharmacologic interventions. For this purpose, polymorphisms need to be investigated not only in relation to disease susceptibility, but also with regard to responsiveness to treatment, and gene-environment interactions. Also, development of novel strategies to comprehensively assess the risk factors particular to the Japanese is warranted. Less