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

利用代谢组学了解有早产史的女性的 CVD 风险

• 批准号: 10211847
• 负责人: KATHRYN M REXRODE
• 金额: $ 77.22万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10211847
• 关键词: Age; Bioinformatics; Biological; Biometry; Blood specimen; Cardiovascular Diseases; Cardiovascular system; Clinical; Collection; Coronary heart disease; Data; Data Collection; Data Set; Development; Diabetes Mellitus; Disease Outcome; Enrollment; Evaluation; Event; Exposure to; Female; Funding; Future; Goals; Hyperlipidemia; Hypertension; Incidence; Individual; Infrastructure; Institutes; Life Cycle Stages; Life Style; Measures; Mediating; Mediation; Medical; Membrane; Metabolic; Methodology; Morbidity - disease rate; Mothers; Nurses' Health Study; Obesity; Outcome; Participant; Pathway interactions; Phenotype; Physiological; Population; Pregnancy; Pregnancy Complications; Pregnancy Histories; Premature Birth; Premature Labor; Prevention strategy; Public Health; Recording of previous events; Research; Research Personnel; Risk; Risk Factors; Risk Marker; Rupture; Sampling; Stroke; System; Testing; Therapeutic Intervention; Time; Validation; Weight Gain; Woman; Women' s Health; adverse pregnancy outcome; cardiovascular disorder risk; cardiovascular risk factor; clinical phenotype; cohort; disorder control; epidemiology study; experience; high risk; improved; liquid chromatography mass spectroscopy; men; metabolomics; middle age; mortality; parous; phenotypic biomarker; prevent; prospective; recruit; study population; success

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.

项目总结/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%的美国怀孕，并与长期妊娠的风险的两倍。 母亲心血管疾病发病率和死亡率。只有13 - 17%的PTD和CVD之间的关联得到解释 通过随后发展确定的心血管危险因素如高血压，糖尿病， 高脂血症和肥胖症。我们对PTD到CVD的生理途径的认识不足， 将PTD用作"早期预警系统"，以更好地预防和治疗女性心血管疾病。这个目标 项目是通过发现和验证代谢组学来扩大我们对PTD和CVD的理解。 有PTD病史的女性的签名和评分，证实其与CVD事件的相关性， 进行中介分析。我们还将研究PTD临床表型与CVD的相关性。 背景：我们组建了一支在心血管疾病、妊娠暴露、 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、妊娠并发症和代谢组学流行病学研究。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，以及 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组学特征。 研究计划：我们将测量1500名女性的代谢组学特征，其中包括400名有糖尿病史的女性。 PTD，和400例经产妇女无早产。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病史的中年女性（NHS 2/3）的PTD代谢产物（M-PTD）评分。PTD 待检查的表型：a）总PTD; B）临床PTD：早产前胎膜破裂， 胎膜完整的自发性早产，医学指征的PTD; c）PTD的时间：<32周，32- <37周;探索性：PTD的不可知衍生代谢物内型; 2）检查 临床PTD表型与CVD发病率（NHS2全数据集）; 3）检验M-PTD的相关性 发生CVD的评分（NHS1、NHS2、WHI），并确定观察到的CVD增加的中介作用 PTD代谢物（NHS 2）的风险。与公共卫生的相关性：心血管疾病是一个重大的公共卫生问题 重要性拟议的分析有可能确定前体和途径不可或缺的CVD PTD后的发病率，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，并产生额外的可检验的假设， 未来的CVD研究我们的方法利用了NHS 2和NHS 3中数十年的前瞻性数据收集 我们的初步数据也证明成功的可能性很大。