Risk Factors for Ischemic Stroke in Women

描述(由申请人提供)：中风是导致残疾和死亡的主要原因，但相对较少的缺血性中风的生化和遗传危险因素已被确定。这项应用的目的是检查女性缺血性中风的新危险因素。缺血性中风的风险与肥胖、胰岛素抵抗和糖尿病密切相关。外源性雌激素明显增加了缺血性中风的风险，最近的证据表明，降低雌激素治疗可以降低中风的风险。脂肪细胞负责类固醇激素的外周转化，并表达可能影响炎症和心血管风险的细胞因子和激素(脂肪因子)。细胞周转率增加和其他因素可能导致端粒长度缩短和愈合能力降低。我们将检验性激素和脂肪因子作为与肥胖和缺血性中风风险相关的新途径。具体地说，我们将测试睾酮、雌二醇、脱氢表雄酮硫酸盐(DHEAS)和性激素结合球蛋白(SHBG)是否可能介导缺血性中风的激素风险。此外，我们还将研究脂肪细胞来源的脂联素和视黄醇结合蛋白4作为女性缺血性中风风险预测因子。此外，还将检测包括LP-PLA2和IL-18在内的内皮炎症标志物。最后，将检测端粒长度，这是生物衰老的标志。护士健康研究(NHS)是1976年对121,700名年龄在30-55岁的美国女性进行的前瞻性队列研究。详细的营养、行为和生活方式变量已经收集了25年以上，有31,926名参与者的存档血液样本(1989-1990年收集)，其中18,700名参与者的第二次样本(2000-2001年收集)。基于通过2008年周期随访预测的病例，我们将分析750对嵌套式缺血性卒中病例对照对的生化标志物和端粒长度。在中风前收集的第二个样本将对其中250对进行分析。在这个队列中，还没有对中风进行生化或遗传学研究。拟议的拨款将在NHS中建立一个单独的中风重点，使我们能够利用详细的数据和大量累积的事件。这些有希望的生化和遗传标记可能对改进预防策略、增强治疗选择和为中风研究产生更多可检验的假说具有意义。公共卫生相关性：女性中风中的缺血性中风的危险因素是导致残疾和死亡的主要原因，但目前确定的缺血性中风的生化和遗传危险因素相对较少。缺血性中风的风险与肥胖、胰岛素抵抗和糖尿病密切相关，这笔赠款将着眼于相关的新风险因素。拟议的拨款将在护士健康研究中建立一个单独的中风重点，利用详细的数据和大量累积的事件。这些有希望的生化和遗传标记可能对改进预防策略、增强治疗选择和为中风研究产生更多可检验的假说具有意义。

DESCRIPTION (provided by applicant): Stroke is a leading cause of disability and death, yet relatively few biochemical and genetic risk factors for ischemic stroke have been identified. The aim of this application is to examine novel risk factors for ischemic stroke in women. The risk of ischemic stroke has been closely associated with obesity, insulin resistance, and diabetes. Exogenous estrogens clearly increase the risk of ischemic stroke and recent evidence suggests a reduced risk of stroke with estrogen lowering therapy. Adipocytes are responsible for peripheral conversion of steroid hormones and express cytokines and hormones (adipokines) that may influence inflammation and cardiovascular risk. Increased cellular turnover and other factors may lead to reduction in telomere length and reduced capacity for healing. We will examine sex hormones and adipokines as novel pathways related to adiposity and risk of ischemic stroke. Specifically, we will test whether testosterone, estradiol, dehydroepiandrosterone sulfate (DHEAS), and sex hormone binding globulin (SHBG) might mediate hormonal risk of ischemic stroke. Additionally, we will examine the adipocyte-derived adiponectin, and retinal binding protein 4 as risk predictors for ischemic stroke in women. Additionally, markers of endothelial inflammation including Lp-PLA2, and IL-18 will be examined. Finally, telomere length, a marker of biologic aging, will be examined. The Nurses' Health Study (NHS) is a prospective cohort study of 121,700 US women, aged 30-55 in 1976. Detailed nutritional, behavioral and lifestyle variables have been collected for more than 25 years, archived blood specimens are available for 31,926 participants (collected1989-1990) and second samples available on 18,700 of these (collected 2000-2001). Based on cases projected through 2008 cycle follow-up, we will analyze 750 nested ischemic stroke case- control pairs for biochemical markers and telomere length. A second sample collected before the stroke will be analyzed on 250 of these pairs. No biochemical or genetic studies for stroke have yet been performed for stroke in this cohort. The proposed grant will establish a separate focus on stroke in the NHS, allowing us to take advantage of the detailed data and large number of events that have accrued. These promising biochemical and genetic markers may have implications for improving prevention strategies, enhancing treatment options and generating additional testable hypotheses for stroke research. PUBLIC HEALTH RELEVANCE: Risk Factors for Ischemic Stroke in Women Stroke is a leading cause of disability and death, yet relatively few biochemical and genetic risk factors for ischemic stroke have been identified. The risk of ischemic stroke has been closely associated with obesity, insulin resistance, and diabetes and this grant will look at related novel risk factors. The proposed grant will establish a separate focus on stroke in the Nurses' Health Study, taking advantage of the detailed data and large number of events that have accrued. These promising biochemical and genetic markers may have implications for improving prevention strategies, enhancing treatment options and generating additional testable hypotheses for stroke research.