Estrogens and pharmacogenetic risks of venous thrombosis in postmenopausal women

说明(申请人提供)：外源性雌激素是一组不同种类的雌激素化合物，包括结合的马雌激素(CEE)、雌二醇(E2)和酯化雌激素(EE)，是一种有争议的潜在有害的药物疗法，但仍被围绝经期和绝经后的妇女继续使用。静脉血栓形成(VT)可能是短期使用雌激素最严重的副作用之一。已经证明，CEE和EE对室性心动过速的风险有不同的影响，CEE是历史上最常用的雌激素。在美国，雌二醇是第二种最常用的口服雌激素，它与室性心动过速风险的关系尚不清楚。这项应用是一项竞争性的更新，以支持在Group Health的一项基于人群的病例对照研究中调查围绝经期和绝经后女性室性心动过速的雌激素和药物遗传风险因素的新工作。最近，Group Health将首选处方雌激素改为E2，这为我们提供了一个独特的机会来表征与这种常用口服雌激素相关的室性心动过速风险。作为我们这次更新的主要目标，我们假设口服E2使用者的VT风险比非雌激素使用者更大，而且，与口服CEE使用者或口服EE使用者相比，口服E2使用者的VT风险更大。作为第二个目标，我们将使用基于实验室的方法来表征健康受试者中口服E2、口服CEE和不使用雌激素的凝血倾向。另一个目的是从越来越多的文献中确定哪些新发现的血栓形成的遗传风险被雌激素的使用所改变。这项研究的背景是华盛顿州的大型综合医疗组织Group Health。研究人群将包括30至89岁的围绝经期和绝经后健康组成员，他们经历过VT事件，要么是深静脉血栓形成，要么是致命或非致命的肺血栓。该应用程序将支持识别和提取发生到2013年的VT病例及其匹配对照的病历数据。血液将被采集，并从那些同意的人身上提取DNA。有关口服雌激素产品安全性的数据有限，阻碍了妇女及其医生在选择雌激素产品治疗更年期血管舒缩症状时做出循证决定。这一竞争更新的目的是利用这一独特而有价值的资源扩大研究，这种资源已经产生了重要的流行病学信息，并可能提供高质量的数据，开始解决妇女健康的重要公共卫生问题。公共卫生相关性：有关口服雌激素产品安全性的数据有限，阻碍了妇女及其医生在选择雌激素产品治疗更年期血管舒缩症状时做出循证决定。静脉血栓形成可能是短期使用雌激素最严重的副作用，但人们几乎对口服雌二醇的风险一无所知，雌二醇是第二种最常用的雌激素。我们建议对绝经后妇女进行一项基于人群的病例对照研究，以检查与口服雌二醇和其他雌激素相关的静脉血栓形成的风险。

DESCRIPTION (provided by applicant): Exogenous estrogens, a heterogeneous group of estrogenic compounds that includes conjugated equine estrogen (CEE), estradiol (E2), and esterified estrogen (EE), are a controversial and potentially harmful pharmaceutical therapy that nonetheless continues to be used by peri- and post-menopausal women. Venous thrombosis (VT) may be one of the most serious side-effect of short-term estrogen use. It has been demonstrated that CEE, historically the most commonly prescribed estrogen, and EE, have differential effects on VT risk. Estradiol is the second most commonly prescribed oral estrogen in the US and its association with VT risk is not known. This application is a competing renewal to support novel work investigating estrogens and pharmacogenetic risk factors for VT in peri- and post-menopausal women in a population-based, case-control study at Group Health. The recent change in the preferred formulary estrogen at Group Health to E2 provides us with a unique opportunity to characterize the VT risk associated with this commonly used oral estrogen. As our primary aim in this renewal, we hypothesize that VT risk is greater in users of oral E2 compared with non-users of estrogen and, moreover, VT risk is greater in oral E2 users compared with oral CEE users or compared with oral EE users. As a secondary aim, we will use laboratory-based measures to characterize the clotting propensity of oral E2, oral CEE, and non-users of estrogen among healthy subjects. An additional aim is to determine which newly identified genetic risks of thrombosis from the growing literature are modified by estrogen use. The setting for the study is Group Health, a large integrated healthcare organization in Washington State. The study population will include peri- and post-menopausal Group Health members 30 to 89 years of age who experienced an incident VT, either deep vein thrombosis or fatal or non-fatal pulmonary embolism. This application will support the identification and the abstraction of medical record data VT cases and their matched controls that occur through 2013. Blood will be collected and DNA abstracted from those who consent. Data on the safety of oral estrogen products are limited and hinder women and their physicians from making evidence-based decisions when choosing an estrogen product to treat vasomotor symptoms of menopause. This competing renewal is designed to expand research using this unique and valuable resource that has already produced important epidemiologic information and will likely provide high-quality data to begin to address important public health questions of women's health. PUBLIC HEALTH RELEVANCE: Data on the safety of oral estrogen products are limited and hinder women and their physicians from making evidence-based decisions when choosing an estrogen product to treat vasomotor symptoms of menopause. Venous thrombosis may be the most serious side-effect of short-term estrogen use yet virtually nothing is known about the risks of oral estradiol, the second most commonly used estrogen. We propose an extension of our population-based, case-control study in post-menopausal women to examine risks of venous thrombosis associated with oral estradiol and other estrogens.