Molecular markers of early cardiometabolic health transitions in the CARDIA study

心脏代谢疾病（CMD）是发病率和死亡率的主要原因，特别是在非洲 美国人CMD起源于青年，目前的努力将CMD预防集中在成年早期， 临床上明显的心血管疾病（CVD）或其危险因素的发展。我们已经确定（1）亚临床- cal CVD存在于儿童和年轻人中，并预测长期不良后果;（2）不良CMD 轨迹出现在成年早期，与中年CVD相关;（3）相对于高加索人，非洲人 美国人对CMD风险的早期恶化表现出更大的心脏肥大/功能障碍;（4） 非裔美国人或高加索人在成年早期的高寿命并不取决于代谢危险因素， 时间CMD风险。这些结果暗示了非裔美国人对CMD反应的病理生理学差异 并呼吁在成年早期进行更具体的代谢失调标志物以进行风险分层。在这场重新- gard，代谢物和胞外RNA（ex-RNA）是循环的，稳定的，功能性的生物分子， 在与CMD相关的组织（肝脏、脂肪、肌肉、心脏）中产生代谢信号。我们最近发现- 老年人中与CMD表型（胰岛素抵抗，肝脏/内脏脂肪）相关的循环ex-RNA 心脏病研究（FHS）中的高加索人。令人惊讶的是，来自FHS的这些前RNA中有几个是阿索- 与儿童胰岛素抵抗和不良代谢产物（支链氨基酸）有关， 计算机分析表明ex-RNA在代谢中的调节作用。因此，代谢物和前RNA 可以敏感地识别早期CMD的整体代谢失调。然而，非洲裔美国人和 在CMD/CVD的代谢组学和前RNA研究中，年轻人的代表性仍然不足， 研究生物学见解和风险分层的新场所。在这里，我们扩展了我们的初步发现- 青年冠状动脉风险发展（CARDIA）研究（1）中的研究结果，以确定 反映一生中心脏代谢健康转变的种族青年;（2）了解如何 这些生物分子影响长期临床疾病，利用长期随访和CVD/CMD结果 在卡迪亚。在约2，400例双腔心绞痛患者（45%为非洲裔美国人;平均年龄32岁）中，我们假设 在成年早期，循环代谢物和前RNA失调将识别出患有低血糖的个体。 长期CMD/CVD风险超过20年。我们将确定成年早期的代谢产物谱， 处于不利终身CMD轨迹的个体以及它们如何影响长期CMD风险（例如，肥胖症，Met- 代谢综合征; SA 1）。我们将研究早期不良代谢产物谱如何影响未来的CVD（心血管疾病）， 肥大、健康、血管钙化、临床结局; SA 2）。最后，根据FHS的结果，我们将 使用系统生物学来理解ex-RNA对整体代谢功能障碍的影响（SA 3）。完成 我们独特的合格的多学科团队将为广泛的公共资源提供共享。 科学界在一个年轻的、具有高终身风险的双胞胎人群中调查CMD和CVD。

Cardiometabolic diseases (CMD) are a major cause of morbidity and mortality, specifically among African Americans. CMD has origins in youth, and ongoing efforts focus CMD prevention to early adulthood, before clinically overt cardiovascular disease (CVD) or its risk factors develop. We have established that (1) subclini- cal CVD is present in children and young adults and forecasts long-term adverse outcomes; (2) adverse CMD trajectories appear in early adulthood and are associated with mid-life CVD; (3) relative to Caucasians, African Americans exhibit greater cardiac hypertrophy/dysfunction in response to early worsening in CMD risk; (4) tra- ditional metabolic risk factors do not identify African Americans or Caucasians in early adulthood with high life- time CMD risk. These results imply pathophysiologic distinctions in how African Americans respond to CMD and call for more specific markers of metabolic dysregulation early in adulthood for risk stratification. In this re- gard, metabolites and extracellular RNAs (ex-RNAs) are circulating, stable, functional biomolecules that inte- grate metabolic signals across tissues relevant to CMD (hepatic, adipose, muscle, cardiac). We recently ob- served circulating ex-RNAs associated with CMD phenotypes (insulin resistance, hepatic/visceral fat) in older Caucasians in the Framingham Heart Study (FHS). Strikingly, several of these ex-RNAs from FHS were asso- ciated with insulin resistance and adverse metabolite profiles (branched chain amino acids) in children, with in silico analysis suggesting a regulatory role for ex-RNAs in metabolism. Therefore, metabolites and ex-RNAs may sensitively identify global metabolic dysregulation early in CMD. Nevertheless, African Americans and young adults remain underrepresented in studies of metabolomics and ex-RNAs in CMD/CVD, representing a novel locus of investigation for biological insights and risk stratification. Here, we extend our preliminary find- ings in the Coronary Artery Risk Development in Youth (CARDIA) study (1) to identify molecular biomarkers in young adulthood across race that reflect cardiometabolic health transitions through life; (2) to understand how these biomolecules impact long-term clinical disease, leveraging long-term follow-up and CVD/CMD outcomes in CARDIA. In ~2,400 biracial CARDIA participants (45% African American; mean age 32), we hypothesize that circulating metabolites and ex-RNAs dysregulated in early adulthood will identify individuals with poor long-term CMD/CVD risk over >20 years. We will determine metabolite profiles in early adulthood that identify individuals in adverse lifetime CMD trajectories and how they impact long-term CMD risk (e.g., adiposity, met- abolic syndrome; SA1). We will investigate how early adverse metabolite profiles impact future CVD (cardiac hypertrophy, fitness, vascular calcification, clinical outcomes; SA2). Finally, following results in FHS, we will use systems biology to understand implications of ex-RNAs on global metabolic dysfunction (SA3). Completion of this project by our uniquely qualified multidisciplinary team will provide a shared public resource to the broad scientific community for investigation of CMD and CVD in a young, biracial population at high lifetime risk.