Risk Factors for Ischemic Stroke

 描述（由申请人提供）：女性受卒中的影响不成比例，女性缺血性卒中的许多最强风险因素与代谢改变有关。然而，这些代谢改变究竟如何直接影响中风的病理生理尚不清楚。代谢组学技术测量小分子代谢物的完整概况，提供个体代谢状态的全面图片。虽然心血管疾病的初步结果是有希望的，但尚未进行中风的前瞻性研究。在本申请中，我们建议在护士健康研究I和护士健康研究II（正在进行的纵向前瞻性队列研究）中评估个体代谢物和代谢组学特征与女性随后缺血性卒中的相关性。拟议的研究将使用存档的空腹血液标本，并结合详细的行为、医学和生活方式变量。一个经过验证的最先进的代谢组学平台将通过液相色谱串联质谱法表征300多种代谢物，并提供非目标数据。利用巢式病例对照设计，将对400例卒中病例及其匹配对照的“发现队列”和300例卒中病例/对照的“验证队列”进行两阶段分析，以鉴定和验证与女性缺血性卒中事件相关的新型代谢物和代谢组学特征。还将在两个外部队列中进行复制。探索性分析将按缺血性卒中亚型比较代谢产物谱。发现新的代谢途径，以前不知道参与中风的发病机制，最终可能导致新的方法来预防一般人群和进一步降低发病率和死亡率中风。

 DESCRIPTION (provided by applicant): Women are disproportionately affected by stroke and many of the strongest risk factors for ischemic stroke in women are associated with altered metabolism. However, exactly how these metabolic alterations directly impact the pathophysiology of stroke is unclear. Metabolomic techniques measure a full profile of small-molecule metabolites, providing a comprehensive picture of an individual's metabolic status. Although preliminary results for cardiovascular disease are promising, no prospective studies for stroke have been conducted. In this application, we propose to evaluate the associations of individual metabolite and metabolomic profiles with subsequent ischemic stroke among women in the Nurses' Health Study I and Nurses' Health Study II, ongoing longitudinal prospective cohort studies. The proposed investigations will use archived fasting blood specimens in concert with detailed behavioral, medical and lifestyle variables. A validated, state-of- the-art metabolomic platform will characterize over 300 metabolites by liquid chromatography tandem mass spectrometry, as well as provide untargeted data. Utilizing a nested case-control design, a two-phase analysis will be conducted with a "discovery cohort" of 400 stroke cases and their matched controls and a "validation cohort" of 300 stroke cases/controls to identify and validate novel metabolite and metabolomic profiles associated with incident ischemic stroke in women. Replication in two external cohorts will also be performed. Exploratory analyses will compare the metabolite profiles by subtype of ischemic stroke. Discovery of novel metabolic pathways not previously known to be involved in the pathogenesis of stroke could ultimately lead to new approaches for prevention in the general population and further reduction in morbidity and mortality from stroke.