Multi-omics for obesity-associated liver disease discovery in Hispanics/Latinos: the Cameron County Hispanic Cohort

西班牙裔/拉丁裔肥胖相关肝病发现的多组学：卡梅伦县西班牙裔队列

基本信息

批准号：
10744625
负责人：
Jennifer Below
金额：
$ 80万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10744625
关键词：
Abdomen Address Adipose tissue Adult Affect Biological Biological Markers Biopsy Blood specimen Collaborations Collection Communities Consent County Data Data Analyses Data Collection Development Disease Disease Progression Elements Enrollment Environmental Exposure Equation Fatty acid glycerol esters Fibrosis Future Generations Genes Genetic Health Hispanic Hispanic Populations Individual Infrastructure Intervention Latino Latino Population Leadership Liver Liver Fibrosis Liver diseases Longitudinal Studies Longitudinal cohort Measures Mediation Mendelian randomization Metabolic Metabolic dysfunction Mexican Americans Modeling Molecular Molecular Profiling Obesity associated liver disease Participant Pathogenesis Pharmacotherapy Phenotype Population Population Heterogeneity Population Study Predisposition Prevalence Production Proteomics Research Risk Factors Science Signal Transduction Site Specimen Technology Time Tissues United States National Institutes of Health Visit Vulnerable Populations Whole Blood Work biomarker discovery cardiometabolic risk chronic liver disease cohort data integration data sharing design elastography experience follow-up global health high risk human disease metabolic-associated fatty liver disease metabolomics multidimensional data multiple omics non-alcoholic fatty liver nonalcoholic steatohepatitis novel phenotypic data preservation prospective response social health determinants subcutaneous transcriptomics

项目摘要

ABSTRACT We submit “Multi-omics for obesity-associated liver disease discovery in Hispanics/Latinos: the Cameron County Hispanic Cohort” (hereafter CCHC-Liver) in response to RFA-HG-22-008, as a disease study site (DSS) that will participate in the Multi-omics for Health and Disease Consortium (hereafter, “the Consortium”). Collectively, this Consortium will advance the science related to use of multi-omics technologies to study health and disease in ancestrally diverse populations. CCHC-Liver will leverage the extant infrastructure of the CCHC, a large, randomly ascertained, exquisitely phenotyped, longitudinal cohort of Hispanic/Latino (HL) participants that have been consented for future contact. We will implement a longitudinal study of liver disease progression, collecting serial specimens and measures of cardiometabolic risk factors (CMRF), social determinants of health (SDH), and of metabolic-associated fatty liver disease (MAFLD), assessed with serial transient elastography (TE) and biomarkers (FIB-4, APRI)] .The umbrella term “MAFLD” encompasses a range of chronic liver diseases, including non-alcoholic fatty liver (NAFLD), non-alcoholic steatohepatitis (NASH), and fibrosis, and has no approved drug therapy. Its prevalence is highest in HL populations, yet, longitudinal omics in accessible tissues for liver disease, namely, whole blood (WB) and abdominal subcutaneous adipose (SAT), are scarce, particularly inthe most vulnerable populations.To address this gap, we propose two Aims. 1) Consortium participation as a disease study site (DSS). Together with the teams from RFA-HG-22-009 [Omics Production Centers (OPCs)] and RFA-HG-22-010 [Data Analysis and Coordination Center (DACC)], we will work collaboratively to complete three operational subaims to: develop best practices for the collection, harmonization, and integration of longitudinal multi-omic, phenotypic, and environmental exposure data; develop best practices for data analysis to detect and assess molecular “profiles” associated with healthy and disease states; and create a multi- dimensional dataset that is available to the research community. 2) Design and implement a study of liver disease progression in an understudied, high-risk HL population. In this aim we will 1) enroll 300 HL participants, 200 with MAFLD and 100 without disease, consented for collection of data, future research use, and broad data sharing from an extant population-based study; 2) collect phenotypic data and biospecimens suitably preserved for omics data generation by OPCs across three time points; 3) submit biospecimens to the OPCs for data production; 4) integrate data to identify changes in WB and SAT multi-omics associated with liver disease progression; 5) perform causal inference in multi-omics to determine associations using Mendelian randomization (MR); 6) combine MAFLD-associated genetic factors with multi-omics measures to evaluate mechanistic frameworks via colocalization; 7) combine SDH and CMRF with multi-omics and MAFLD to assess causal mediation; 8) characterize novel multi-omics signals via structural equation modeling; and 9) determine global and local ancestry effects on multi-omics associated with liver disease progression.

抽象的我们提交了“西班牙裔/拉丁裔肥胖相关肝病发现的多组学：卡梅伦县西班牙裔群体”（以下简称 CCHC-Liver）响应 RFA-HG-22-008，作为疾病研究网站（DSS）将参加健康与疾病多组学联盟（以下简称“联盟”）。总的来说，该联盟将推进与使用多组学技术研究健康相关的科学 CCHC-Liver 将利用 CCHC 的现有基础设施，大量、随机确定、表型精确的纵向队列西班牙裔/拉丁裔 (HL) 参与者已同意将来进行接触，我们将实施一项肝脏疾病进展的纵向研究，收集系列样本并测量心脏代谢危险因素 (CMRF)、健康的社会决定因素 (SDH) 和代谢相关脂肪性肝病 (MAFLD)，通过连续瞬时弹性成像进行评估 (TE) 和生物标志物 (FIB-4、APRI)]。总括术语“MAFLD”涵盖一系列慢性肝病、包括非酒精性脂肪肝（NAFLD）、非酒精性脂肪性肝炎（NASH）和纤维化，并且没有批准的药物治疗在 HL 人群中的患病率最高，但在可及组织中进行纵向组学研究。对于肝脏疾病，即全血（WB）和腹部皮下脂肪（SAT），稀缺, 特别为了解决这一差距，我们提出了两个目标 1) 联盟参与。作为疾病研究中心 (DSS) 与 RFA-HG-22-009 [组学生产中心] 的团队一起。 (OPC)] 和 RFA-HG-22-010 [数据分析和协调中心 (DACC)]，我们将共同努力完成三个运营子目标：制定收集、协调和整合的最佳实践纵向多组学、表型和环境暴露数据；开发数据分析的最佳实践；检测和评估与健康和疾病状态相关的分子“谱”； 2) 设计并实施肝脏研究未充分研究的高危 HL 人群中的疾病进展为了实现这一目标，我们将 1) 招募 300 名 HL。参与者（200 名患有 MAFLD 和 100 名没有疾病）同意收集数据、未来的研究用途，以及现有基于人群的研究的广泛数据共享；2) 收集表型数据和生物样本；适当保存以供 OPC 在三个时间点生成组学数据 3) 将生物样本提交给用于数据生成的 OPC；4) 整合数据以识别与肝脏相关的 WB 和 SAT 多组学变化疾病进展；5) 使用孟德尔在多组学中进行因果推断以确定关联随机化（MR）；6）将MAFLD相关遗传因素与多组学措施结合起来进行评估通过共定位建立机制框架；7) 将 SDH 和 CMRF 与多组学和 MAFLD 结合起来进行评估因果中介；8) 通过结构方程模型表征新颖的多组学信号；9) 确定全球和局部血统对与肝病进展相关的多组学的影响。