Hyperglycemia and Adverse Pregnancy Outcome Study-Cardiovascular Health of HAPO Offspring (HAPO CVH)

项目摘要 阻止心血管疾病(CVD)风险的代际转移是NHLBI和 美国心脏协会(AHA)。然而，对时间、途径和机制的了解有限 母体妊娠健康和子代心血管健康之间已观察到的联系 (CVH)仍然是制定有针对性、及时干预措施的重大障碍。我们建议利用 高血糖与不良妊娠结局(HAPO)研究队列研究大幅提高理解 子代CVH和CVD的宫内起源，在青壮年的关键时期测量。这个 最初的HAPO研究在2000-2006年间招募了约25,500名女性，前瞻性地统一检查 未经治疗的妊娠期血糖与母婴结局的关系。十一 几年后，4832名子女返回研究妊娠期糖尿病对子女肥胖和血糖的影响。我们假设 怀孕28周的孕妇肥胖、血糖、血压和血脂之间存在显著的独立关联 18-25岁子代的CVH妊娠和动脉损伤以及DNA甲基化(DNaM) 将与上游宫内暴露、下游CVH和动脉损伤相关。Hapo CVH 将包括对来自4个HAPO中心的1,000个HAPO FU后代进行的全面CVH评估。我们会 测量血压、肥胖、血脂、血糖和生活方式行为，用AHA‘s’s Simple‘s来描述总的CVH 7‘框架，并获得颈动脉超声图像，以识别亚临床CVD的最早变化。我们还将 分析现有的脐带血dNaM数据，并将从年轻人那里获得新的表观基因组关联数据 DNA使用Illumina 850K芯片。我们将通过以下具体目标实现我们的目标： 目的1：明确妊娠~28周宫内心脏代谢环境与子代CVH的关系 和亚临床脑血管病在青壮年。假设1a：孕妇的妊娠代谢健康状况较差 与年轻时较差的子代CVH(共同初级结局)有关。假设1b：更穷 孕妇孕期代谢健康与较高的颈动脉IMT(共同主要结局)、较低的颈动脉相关 可扩张性，以及青年时期不良的颈动脉灰阶特征。假设1c：更贫穷 母亲孕期代谢健康与心血管健康从儿童到 青壮年。具体目标2：审查表观遗传机制在上游的关联中的作用 宫内心脏代谢暴露和下游CVH和亚临床心血管疾病。假设2a：更贫穷 母亲孕期代谢健康与衰老相关途径中不同的dNaM有关(测量 如表观遗传老化加速)在脐带血和年轻成年后代中。假设2b：较贫穷的母亲 妊娠期代谢健康与特定心脏代谢途径的不同dNaM有关 成体后代血细胞，这种差异的dNaM在统计上部分地介导了不利的 青壮年宫内暴露与晚期CVH状态和颈动脉损伤

Project Summary Halting the intergenerational transfer of cardiovascular disease (CVD) risk is a priority for NHLBI and the American Heart Association (AHA). Yet, limited understanding around the timing, pathways, and mechanisms underlying the observed associations between maternal gestational health and offspring cardiovascular health (CVH) remains a significant barrier to developing targeted, timely interventions. We propose to leverage the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study cohort to substantially advance understanding of the in utero origins of offspring CVH and CVD, as measured during the critical period of young adulthood. The original HAPO study recruited ~25,500 women in 2000-2006 to prospectively and uniformly examine the association of gestational glycemia, uncomplicated by treatment, with maternal and neonatal outcomes. Eleven years later, 4,832 offspring returned to study effects of GDM on offspring adiposity and glycemia. We hypothesize that there are significant independent associations of maternal adiposity, glycemia, BP, and lipids at ~28 weeks gestation with CVH and arterial injury among offspring at age 18-25 years, and that DNA methylation (DNAm) will be associated with upstream intrauterine exposures and downstream CVH and arterial injury. HAPO CVH will include a comprehensive CVH assessment of 1,000 HAPO FUS offspring from 4 HAPO centers. We will measure BP, adiposity, lipids, glycemia, and lifestyle behaviors, characterize total CVH with AHA’s ‘Life’s Simple 7’ framework, and obtain carotid ultrasonography to identify the earliest changes of subclinical CVD. We will also analyze existing cord blood DNAm data and will acquire new epigenome-wide association data from young adult DNA using the Illumina 850K chip. We will achieve our objectives through the following specific aims: Specific Aim 1: Define associations of the in utero cardiometabolic milieu at ~28 weeks’ gestation with offspring CVH and subclinical CVD in young adulthood. Hypothesis 1a: Poorer maternal gestational metabolic health is associated with poorer offspring CVH (Co-primary outcome) in young adulthood. Hypothesis 1b: Poorer maternal gestational metabolic health is associated with higher carotid IMT (Co-primary outcome), lower carotid distensibility, and unfavorable carotid artery grayscale features in young adulthood. Hypothesis 1c: Poorer maternal gestational metabolic health is associated with worsening of cardiovascular health from childhood to young adulthood. Specific Aim 2: Examine the role of epigenetic mechanisms in the association of upstream intrauterine cardiometabolic exposures and downstream CVH and subclinical CVD. Hypothesis 2a: Poorer maternal gestational metabolic health is associated with differential DNAm in aging-related pathways (measured as accelerated epigenetic aging) in cord blood and young-adult offspring. Hypothesis 2b : Poorer maternal gestational metabolic health is associated with differential DNAm in specific cardiometabolic pathways in young- adult offspring blood cells, and this differential DNAm partly statistically mediates the association of adverse intrauterine exposures with later CVH status and carotid arterial injury in young adulthood