Individual Propensity to Venous Thrombosis

描述(由申请人提供)：我们的总体长期目标是确定复杂(多因素)疾病的危险因素，静脉血栓栓塞症(VTE)。我们将检查候选基因和循环促凝血活性，以确定它们是否与VTE有关。我们的具体目标是：目标1：识别大量候选基因中的功能性SNPs/Ht-SNPs，并测试这些SNPs/Ht-SNPs与VTE的关联。使用已知的以基因为中心的DMA变异体的高通量基因分型(n=5000)，我们将测试抗凝、促凝、纤溶和急性全身炎症途径中的大量候选基因(n=300)。目的2：确定复杂的候选基因交互作用是否与静脉血栓栓塞症相关。连锁不平衡将用于识别来自中西部的1500例临床特发性静脉血栓栓塞症病例和1500例在患者年龄、性别和居住地县频率匹配的无关对照中的单倍型标记SNPs。使用来自AIM 1的数据，我们将应用单SNP和单倍型分析来识别与VTE相关的特定变异体和变异组。我们还将研究这些易感基因对VTE的联合作用；以及目标3：确定循环全血促凝活性的功能分析是否与VTE相关，包括遗传交互作用。我们将使用全球功能分析来前瞻性地在我们的临床VTE病例(n=300)和对照(n=600)样本中测试这种活动与VTE的相关性，包括遗传交互作用。VTE是一个主要的国家健康问题，在美国每年有超过275,000起事件，仅治疗费用每年就花费超过73亿美元(按1999年美元计算)。由于四分之一的PE患者表现为猝死，因此必须降低VTE的发生率以提高存活率。然而，自1980年以来，静脉血栓栓塞症的发病率一直相对稳定在每1000人中有1人左右。显然，需要更好的预防VTE的方法。

DESCRIPTION (provided by applicant): Our overall long-term goal is to determine risk factors for the complex (multifactorial) disease, venous thromboembolism (VTE). We will examine both candidate genes and circulating procoagulant activity to determine if they are associated with VTE. Our specific aims are: Aim 1: To identify functional SNPs/ht- SNPs within a large set candidate genes and test these SNPs/ht-SNPs for an association with VTE. Using high throughput genotyping of known gene-centric DMA variants (n=5000), we will test a large set of candidate genes (n=300) within the anticoagulant, procoagulant, fibrinolytic, and acute systemic inflammation pathways. Linkage disequilibrium will be used to identify haplotype-tagging SNPs within 1,500 clinic-based, idiopathic VTE cases from the Midwest, and 1500 unrelated controls frequency-matched on patient age, gender, and county of residence; Aim 2: To determine if complex candidate gene interactions are associated with VTE. Using data from aim 1, we will apply single SNP and haplotype analyses to identify specific variants and groups of variants associated with VTE. We will also investigate the joint effects of these susceptibility genes on VTE stratified on Factor V Leiden; and Aim 3: To determine if functional assays of circulating whole blood procoagulant activity associate with VTE, including genetic interactions. We will use global functional assays to prospectively test such activity for an association with VTE in a sample of our clinic-based VTE cases (n=300) and controls (n=600), including genetic interactions. VTE is a major national health problem, with over 275,000 incident cases per year in the United States and costing over $7.3 billion (in 1999 dollars) per year for treatment charges alone. Since one-quarter of PE patients present as sudden death, the incidence of VTE must be reduced in order to improve survival. However, the incidence of VTE has remained relatively constant at about 1 per 1000 since 1980. Clearly, better methods of targeting VTE prophylaxis are needed.