Inflammatory mediators of cardiometabolic risk in Latinos

摘要 心脏代谢危险因素和2型糖尿病(T2D)使发病率和死亡率大幅上升 不成比例地影响到种族/族裔少数群体，包括西班牙裔/拉丁裔的负担(H/L)。人口 负担、已建立的差异和T2D治疗的有限可获得性，以逆转进展或预防长期- 术语复杂性强调迫切需要澄清可能作为新靶点的机械性途径 用于预防和治疗。慢性低度炎症是公认的常见病理改变。 心脏代谢危险因素和T2D的特征，特别是H/L与其他种族/民族的比较 小组；识别慢性低度炎症的特定介质可以极大地增强为 现有药物或新疗法的开发，特别是在高危人群中。之前的检查尝试 慢性低度炎症的特定介质一直受到下游标志物的关注， 包括C反应蛋白，它们不太可能是因果关系，或者很难可靠地测量。上游 全身性炎症的调节又是由脂肪酸衍生的脂类介体介导的，称为二十烷基类化合物。 尽管某些二十烷类化合物与心脏代谢风险因素和T2D有关，但先前的研究已经 只评估了几种在人类中含量最丰富的二十烷类化合物。我们建议解决这一重大问题 通过利用分析质谱学(MS)的进步来实现研究差距，这使得现在能够快速和 准确定量跨越主要生物合成途径的&gt；150二十烷类化合物。二十烷类化合物将被检测 在深入表型的基于人群的拉美裔社区健康研究/拉美裔(SOL)队列研究中， 在存在心脏代谢风险的H/L人群中实现研究假设的成本效益测试 因子和T2D差异。具体地说，我们将确定已知的和新的与以下物质相关的二十烷类化合物 心脏代谢风险因素和T2D，以及利用现有基因组数据进行因果推断 研究和评估关键二十烷类化合物的机械框架。这项工作将使我们深入了解 H/L心脏代谢性疾病的潜在机制，确定健康差异的潜在来源 基因混合的队列，并为未来炎症调节的研究提供必要的基础 旨在减轻广大人群心脏代谢性疾病负担的治疗方法。

ABSTRACT Cardiometabolic risk factors and type 2 diabetes (T2D) impart a substantial and growing morbidity and mortality burden that disproportionally affects racial/ethnic minorities, including Hispanic/Latinos (H/L). The population burden, established disparities, and limited availability of T2D treatments to reverse progression or prevent long- term complications underscore an urgent need to clarify mechanistic pathways that may serve as novel targets for prevention and treatment. Chronic low-grade inflammation is a widely recognized common pathological feature underling cardiometabolic risk factors and T2D, particularly in H/L when compared to other racial/ethnic groups; identifying specific mediators of chronic low-grade inflammation could greatly enhance efforts to tailor existing agents or develop of novel therapies, especially in populations at highest risk. Prior attempts to examine specific mediators of chronic low-grade inflammation have been limited by a focus on downstream markers, including C-reactive protein, which are less likely to be causal or are difficult to reliably measure. Upstream regulation of systemic inflammation is in turn mediated by fatty acid derived lipid mediators termed eicosanoids. Although select eicosanoids have been associated with cardiometabolic risk factors and T2D, prior studies have only assessed a handful of the most abundant eicosanoids in humans. We propose to address this major research gap by leveraging advances in analytical mass spectrometry (MS) that now enable the rapid and accurate quantification of >150 eicosanoids spanning major biosynthetic pathways. Eicosanoids will be assayed in the deeply-phenotyped population-based Hispanic Community Health Study/Study of Latinos (SOL) cohort, enabling cost-effective testing of study hypotheses in a H/L population with established cardiometabolic risk factor and T2D disparities. Specifically, we will identify known and novel eicosanoids associated with cardiometabolic risk factors and T2D, as well as leverage existing genomics data to conduct causal inference studies and evaluate mechanistic frameworks for key eicosanoids. This work will shed insight into the mechanisms underlying cardiometabolic disease in H/L, identify potential sources of health disparities in a genetically admixed cohort, and provide an essential foundation for future studies of inflammatory-modulating therapies aimed at reducing the burden of cardiometabolic disease in the population at large.