Using Metabolomics to Understand CVD Risk in Women with a History of Preterm Delivery

项目摘要/摘要 背景：心血管疾病(CVD)是女性和男性死亡的主要原因。 早产(PTD)发生在10%的美国孕妇中，并且与长期妊娠风险的两倍相关 母亲心血管疾病发病率和死亡率。只有13-17%的人解释了PTD和CVD之间的联系 通过随后发展已确立的心血管危险因素，如高血压，糖尿病， 高脂血症和肥胖。我们对从PTD到CVD的生理通路的缺乏了解限制了我们的 有能力利用PTD作为“早期预警系统”，更好地预防和治疗妇女的心血管疾病。这样做的目的是 项目是通过发现和验证代谢组来扩大我们对PTD和CVD的理解 有PTD病史的女性的签名和得分，证实她们与心血管疾病事件和 执行调解分析。我们还将研究PTD临床表型与心血管疾病的关系。 环境：我们组建了一支出色的团队，在心血管疾病、怀孕暴露、 代谢组学和生物统计学/生物信息学。这个项目的调查人员有几十年的经验 研究心血管疾病、妊娠并发症和代谢流行病学研究。此应用程序将 利用U01资助的基础设施和护士健康研究(NHS)2和3队列的生物样本 作为心血管疾病的结果和先前在NHS1和妇女健康倡议中测量的代谢特征。 研究计划：我们将测量1500名女性的代谢谱，其中包括400名有 PTD，以及400名没有早产的临产妇女。代谢组学将在布罗德研究所进行。 使用强大的发现和验证方法，我们将：1)发现和验证代谢组学 有PTD病史的中年妇女的资料和PTD代谢物(M-PTD)评分(NHS2/3)。PTD 要检查的表型：a)总PTD；b)临床PTD：早产、早产、胎膜破裂， 自发性早产，胎膜完整，医学显示为PTD；c)PTD的时间：&lt；32周，32- 37周；探索性：未知来源的PTD代谢物内型；2)检查 临床PTD表型与CVD发病率(NHS2全数据集)；3)测试M-PTD的关联性 对发生的心血管疾病(NHS1、NHS2、WHI)进行评分，并确定观察到的心血管疾病增加的中介 PTD代谢物的风险(NHS2)。与公共卫生的相关性：心血管疾病是一个重大公共卫生问题 重要性。拟议的分析有可能确定心血管疾病的前驱物质和途径 PTD后的发病率，这是女性特有的心血管危险因素，然后可以用来改善 预防策略，增强治疗选择，并产生更多可测试的假设，以指导 未来的心血管疾病研究。我们的方法利用了NHS2和NHS3数十年的前瞻性数据收集 我们强劲的初步数据支持成功的可能性很高。

Project Summary/Abstract Background: Cardiovascular disease (CVD) is the leading cause of mortality in both women and men. Preterm delivery (PTD) occurs in 10% of US pregnancies and is associated with twice the risk of long-term CVD morbidity and mortality in mothers. Only 13-17% of the association between PTD and CVD is explained by subsequent development of established cardiovascular risk factors such as hypertension, diabetes, hyperlipidemia and obesity. Our poor understanding of the physiologic pathways from PTD to CVD limits our ability to use PTD as an `early warning system' to better prevent and treat CVD in women. The goal of this project is to expand our understanding of PTD and CVD through discovery and validation of metabolomic signatures and scores among women with a history of PTD, confirming their association with CVD events and performing mediation analysis. We will also examine the association of PTD clinical phenotypes with CVD. Setting: We have assembled an exceptional team with deep expertise in CVD, pregnancy exposures, metabolomics, and biostatistics/ bioinformatics. Investigators on this project have decades of experience studying CVD, pregnancy complications, and metabolomic epidemiological studies. This application will leverage U01-funded infrastructure and biosamples of the Nurses' Health Study (NHS) 2 and 3 cohorts, as well as CVD outcomes and previously measured metabolomic profiles in NHS1 and the Women's Health Initiative. Research Plan: We will measure metabolomic profiles in 1500 women, including 400 women with a history of PTD, and 400 parous women with no preterm deliveries. Metabolomics will be performed at the Broad Institute. Using a robust methodology of discovery and validation, we will: 1) Discover and validate metabolomic profiles and PTD metabolite (M-PTD) scores for midlife women with a history of PTD (NHS2/3). PTD phenotypes to be examined: a) Total PTD; b) Clinical PTD: Preterm prelabor rupture of membranes, spontaneous preterm labor with intact membranes, medically-indicated PTD; c) Timing of PTD: <32 weeks, 32- <37 weeks; Exploratory: Agnostically derived metabolite endotypes of PTD; 2) Examine the association of clinical PTD phenotypes with CVD incidence (NHS2 full dataset); 3) Test the association of M-PTD scores with incident CVD (NHS1, NHS2, WHI) and determine mediation of the observed increased CVD risk from PTD metabolites (NHS2). Relevance to Public Health: CVD is an issue of major public health importance. The proposed analyses have the potential to identify precursors and pathways integral to CVD incidence after PTD, a female-specific cardiovascular risk factor, which may then be used to improve prevention strategies, enhance treatment options, and generate additional testable hypotheses that will guide future CVD research. Our approach leverages decades of prospective data collection in the NHS2 and NHS3 and our strong preliminary data support a high likelihood of success.