Inflammatory mediators of cardiometabolic risk in Latinos

摘要 心脏代谢风险因素和2型糖尿病（T2 D）导致了大量且不断增长的发病率和死亡率 对种族/少数民族造成不利影响的负担，包括西班牙裔/拉丁裔（H/L）。人口 负担、既定差异以及T2 D治疗逆转进展或预防长期 长期并发症强调迫切需要澄清可能作为新靶点的机制途径 来预防和治疗。慢性低度炎症是一种公认的常见病理性疾病， 与其他人种/种族相比，存在潜在的心脏代谢风险因素和T2 D，尤其是H/L 组;确定慢性低度炎症的特定介质可以大大提高定制 现有药物或开发新型疗法，特别是在高风险人群中。先前尝试检查 慢性低度炎症的特异性介质受到下游标志物的限制， 包括C-反应蛋白，它们不太可能是因果关系或难以可靠地测量。上游 全身炎症的调节又由称为类二十烷酸的脂肪酸衍生的脂质介质介导。 尽管选择的类二十烷酸与心脏代谢风险因素和T2 D相关，但先前的研究 只评估了人类中最丰富的几种类二十烷酸。我们建议解决这一重大问题， 利用分析质谱（MS）的进步，现在可以快速， 准确定量跨越主要生物合成途径的>150种类二十烷酸。将测定类花生酸 在基于深度表型人群的西班牙裔社区健康研究/拉丁美洲人研究（SOL）队列中， 在具有已确定心脏代谢风险的H/L人群中进行研究假设的成本效益检验 因素和T2 D差异。具体来说，我们将确定已知的和新的类二十烷酸与 心脏代谢风险因素和T2 D，以及利用现有基因组学数据进行因果推断 研究和评估关键类花生酸的机制框架。这项工作将有助于深入了解 H/L心脏代谢疾病的潜在机制，确定健康差异的潜在来源， 基因混合队列，并为未来的炎症调节研究提供必要的基础。 旨在减轻广大人群心脏代谢疾病负担的治疗。

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.