Hispanic Latino Lipid Consortium

西班牙裔拉丁裔脂质协会

• 批准号: 10681803
• 负责人: Jennifer Below
• 金额: $ 72.96万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681803
• 关键词: Abdomen; Address; Adipose tissue; African; American Indians; Cardiometabolic Disease; Central obesity; County; Data; Data Set; Diagnostic; Disease Progression; Dyslipidemias; Equilibrium; Etiology; Funding; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic; Genetic Research; Genomics; Goals; Health; Hispanic; Hispanic Community Health Study/Study of Latinos; Hispanic Populations; Hypertension; Individual; Intervention; Latino; Latino Population; Link; Lipids; Longitudinal Studies; Measures; Mendelian randomization; Metabolic; Methods; Mexican; Mission; Molecular; Molecular Profiling; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Paper; Participant; Pathogenesis; Pathway interactions; Patient Recruitments; Pattern; Persons; Pharmacologic Substance; Population; Population Study; Prevention; Publications; Publishing; RNA; Research; Resources; Risk Factors; Role; Sampling; Serum; Signal Transduction; Specimen; Time; Tissue Sample; Tissues; Transcriptional Regulation; Translations; Underrepresented Populations; United States; United States National Institutes of Health; Validation; Variant; Vulnerable Populations; Whole Blood; Work; burden of illness; cardiometabolic risk; cardiometabolism; cell type; clinically relevant; cohort; design; differential expression; disorder prevention; disorder risk; epidemiologic data; experience; follow-up; genetic analysis; genetic risk factor; genome wide association study; genome-wide; genomic data; health disparity; innovation; insight; marginalized population; novel; precision medicine; recruit; sample collection; subcutaneous; success; trait; transcriptome sequencing; transcriptomics; translational pipeline

ABSTRACT Cardiometabolic diseases (CMD), including obesity, dyslipidemia, type 2 diabetes, and hypertension, are the leading cause of disease burden in the world with a disproportionate impact on historically marginalized populations. In the first funding period of our project, The Hispanic/Latino Lipid Consortium (HLLC), our efforts centered on discovering genetic factors impacting serum lipid levels, obesity, and T2D in self-identified Hispanic/Latinos (HL), a population with significant CMD health disparities. This highly impactful research, which has resulted in 39 published papers to-date, leveraged extant genetic data as well as new genetic data generated for the project in >63k participants to identify multiple new CMD loci. We also characterized the regulatory mechanisms influencing lipid levels using a new resource of whole blood (WB) gene expression profiles in 880 HL participants. Yet, the mechanism of action of most GWAS signals and the molecular pathways disrupted in metabolic tissues are still not well understood. As such, in the second funding period of the HLLC, we propose to build on our remarkable success and experience generating and analyzing transcriptomic data in HL. Here, we aim to investigate the role of multi-tissue gene expression (WB and subcutaneous adipose tissue [SAT]) and changes in WB expression over time with the goal of identifying key modifiable molecular signatures associated with CMDs in an even larger, more diverse sample of HL. Specifically, we propose to: first, identify multi-tissue transcriptomic patterns associated with CMD and related traits (obesity, type 2 diabetes, dyslipidemia, hypertension measures) in recently acquired WB RNA sequencing data from 14k HL participants as well as in 300 SAT tissue specimens from HL participants recruited for the present application; second, identify longitudinal changes in WB transcriptomic data associated with changes in CMD-related risk factors in participants from the HLCC (1500 RNA measures from 750 participants with an average of 5 years between the two RNA sequencing measures for each person); and third, conduct integrative analyses of genetic and transcriptomic data to establish causality via Mendelian Randomization and characterize existing genomic findings with functional evidence. Our aims are entirely independent, exceptionally well powered, and designed to answer critical questions about the causal pathways underlying observed transcriptomic differences in CMD. This work will result in creation of a publicly available resource of eQTL information for metabolic tissues in HL and identify novel targets for early prevention and pharmaceutical intervention. Significantly, by addressing CMD risk in an under-represented population, our work contributes directly to the NIH’s mission to promote disease prevention and treatment in historically marginalized populations.

抽象的 心脏代谢疾病（CMD），包括肥胖、血脂异常、2 型糖尿病和高血压，是 世界上疾病负担的主要原因，对历史上被边缘化的人群产生不成比例的影响 人口。在我们的西班牙裔/拉丁裔脂质联盟 (HLLC) 项目的第一个资助期内，我们的努力 重点是发现影响自我识别的血脂水平、肥胖和 T2D 的遗传因素 西班牙裔/拉丁裔 (HL)，CMD 健康差异显着的人群。这项极具影响力的研究， 迄今为止，利用现有遗传数据以及生成的新遗传数据，已发表 39 篇论文 该项目在超过 63,000 名参与者中识别多个新的 CMD 基因座。我们还描述了监管 [第 880 章] HL 参与者。然而，大多数 GWAS 信号的作用机制和分子途径 代谢组织中的破坏仍不清楚。因此，在第二个资助期 HLLC，我们建议以我们非凡的成功和生成和分析转录组的经验为基础 HL 中的数据。在这里，我们的目的是研究多组织基因表达（WB和皮下脂肪）的作用 组织 [SAT]）以及 WB 表达随时间的变化，目的是识别关键的可修饰分子 与更大、更多样化的 HL 样本中的 CMD 相关的签名。具体来说，我们建议： 首先，确定与 CMD 和相关特征（肥胖、2 型 最近从 14k HL 获取的 WB RNA 测序数据中的糖尿病、血脂异常、高血压测量值 参与者以及为本申请招募的 HL 参与者的 300 个 SAT 组织样本； 其次，确定与 CMD 相关风险变化相关的 WB 转录组数据的纵向变化 HLCC 参与者的因素（来自 750 名参与者的 1500 个 RNA 测量，平均 5 年 每个人的两次 RNA 测序测量之间）；第三，进行遗传综合分析 和转录组数据，通过孟德尔随机化建立因果关系并表征现有基因组 具有功能性证据的发现。我们的目标是完全独立的、动力十足且经过精心设计 回答有关观察到的 CMD 转录组差异背后的因果途径的关键问题。 这项工作将创建一个公开可用的 HL 代谢组织 eQTL 信息资源 并确定早期预防和药物干预的新目标。值得注意的是，通过解决 CMD 我们的工作直接有助于 NIH 促进疾病传播的使命 历史上边缘化人群的预防和治疗。