Thrombosis Gene Polymorphisms and Early CHD Risk in HERS

HERS 中的血栓形成基因多态性和早期 CHD 风险

• 批准号: 6684154
• 负责人: DAVID McLeod HERRINGTON
• 金额: $ 33.64万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-12-01 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6684154
• 关键词: cardiovascular disorder risk; coronary disorder; drug interactions; estrogens; female; fibrinogen; gene environment interaction; genetic polymorphism; genetic screening; genetic susceptibility; genotype; glycoproteins; hormone therapy; human tissue; iatrogenic disease; myocardial infarction; patient oriented research; plasminogen activator inhibitors; platelets; point mutation; postmenopause; progestins; protein C; prothrombin; triglycerides; venous thrombosis; women' s health

DESCRIPTION (provided by applicant): The Heart and Estrogen/progestin Replacement Study (HERS) and several other clinical studies and clinical trials have observed a transient increase in risk for coronary heart disease (CHD) events after initiation of hormone replacement therapy (HRT). Some evidence suggests that this adverse effect of HRT may be limited to a subgroup of women who are uniquely at risk for a thrombotic complication of estrogen therapy. There are several well-described polymorphisms in genes whose products regulate coagulation or fibrinolysis that could augment thrombotic risk in the setting of estrogen therapy. These polymorphisms include Factor V Leiden, prothrombin 20210A, Factor VII R353Q. plasminogen activator inhibitor-1 (PAI-1) 4G/5G, fibrinogen B-beta-455A, and platelet GP IIIa P1-A1.A2. We propose a nested case-control study among HERS women with CHD (n = 361) or venous thrombotic events (VTEs) (n = 95) and two clinic-matched controls to assess the relation between the above listed polymorphisms, HRT, and risk for CHD or VTEs. We will estimate the absolute and relative risk of HRT among women with and without the six candidate thrombosis gene polymorphisms and test for evidence of a genotype * HRT interaction. In secondary analyses, we will focus on events that occurred in the first year, evaluate the effect of triglycerides on risk associated with the Factor VII and PAI-1 polymorphisms, and explore the impact of combinations of polymorphisms on risk. DNA for this project will be acquired from centrally stored Pap smears that were collected during the trial. If this project reveals a high-risk subgroup based on thrombosis gene polymorphisms, women could be screened for this condition and cautioned not to use HRT. Conversely, low-risk women might be able to use HRT more safely in pursuit of various health benefits, including a possible reduction in CHD risk. Thus, this project may lead to more effective strategies to prevent CHD in women, enhance the safety of HRT, and add to the expanding body of knowledge concerning drug/gene interactions as they relate to treatment and prevention of disease.

描述（由申请人提供）：心脏和雌激素/孕激素 替代研究（HERS）和其他几项临床研究和临床试验 观察到冠心病（CHD）风险的短暂增加 开始激素替代治疗（HRT）后发生的事件。一些证据 表明HRT的这种不良影响可能仅限于一个妇女亚组 他们是雌激素治疗中唯一面临血栓并发症风险的人。 在基因中有几种被充分描述的多态性，其产物调节 凝血或纤维蛋白溶解可能增加血栓形成的风险 雌激素疗法这些多态性包括凝血因子V Leiden、凝血酶原 20210 A，因子VII R353 Q。纤溶酶原激活物抑制剂-1（派-1）4G/5G， 纤维蛋白原B-β-455A和血小板GP IIIa P1-A1.A2。我们提出了一个嵌套的 在患有CHD（n = 361）或静脉血栓形成的HERS女性中进行的病例对照研究 事件（VTE）（n = 95）和两个临床匹配的对照，以评估 以上列出的多态性、HRT和CHD或VTE风险之间的关系。我们将 估计HRT的绝对和相对风险的妇女和没有 六个候选血栓形成基因多态性和基因型证据测试 * HRT相互作用。在二次分析中，我们将重点关注发生在 在第一年，评估甘油三酯对与以下相关风险的影响： 因子VII和派-1多态性，并探讨组合的影响 多态性对风险的影响。该项目的DNA将从中央采购， 储存试验期间收集的巴氏涂片。 如果这个项目揭示了一个基于血栓形成基因的高危亚组， 多态性，妇女可以筛查这种情况，并告诫不要 使用HRT。相反，低风险妇女可能能够更安全地使用HRT， 追求各种健康益处，包括可能降低CHD风险。 因此，该项目可能会导致更有效的策略，以预防冠心病， 妇女，提高HRT的安全性，并增加了不断扩大的知识体系 关于药物/基因相互作用，因为它们涉及治疗和预防 疾病