Hispanic Latino Lipid Consortium

西班牙裔拉丁裔脂质协会

基本信息

批准号：
10112293
负责人：
Jennifer Below
金额：
$ 77.05万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10112293
关键词：
Accounting Adult African American Age Architecture Atherosclerosis Biological Biology Cardiovascular Diseases Caucasians Cholesterol Chronic Disease Clinic Clinical Complex Computerized Medical Record County DNA Data Dyslipidemias Ensure Epidemiology Ethnic group European Exhibits Functional disorder Gall Bladder Diseases Gene Expression Genes Genetic Genetic Predisposition to Disease Genetic Research Genetic study Genomics Health Health system Heritability High Density Lipoprotein Cholesterol Hispanics Human International Classification of Disease Codes Investigation Knowledge LDL Cholesterol Lipoproteins Latin America Latino Link Lipids Maps Medical History Medicine Metabolism Not Hispanic or Latino Outcome Participant Pathway interactions Patients Phenotype Population Population Heterogeneity Populations at Risk Positioning Attribute Precision therapeutics Prevalence Proteins Public Health Regulation Reporting Research Research Personnel Risk Sampling Serum Structure Tissues Transcript Translating Triglycerides Underrepresented Populations United States Centers for Medicare and Medicaid Services Validation Variant Work barrier to care base biobank cardiovascular disorder risk causal variant clinically significant clinically translatable cohort design differential expression disorder prevention disorder risk genetic epidemiology genetic predictors genetic risk factor genetic variant genome wide association study genome-wide genomic locus high risk individualized prevention insight multi-ethnic non-alcoholic fatty liver non-alcoholic fatty liver disease novel personalized intervention phenome precision medicine predict clinical outcome racial and ethnic rare variant repository risk stratification success therapeutic target trait transcriptome sequencing translational genomics translational pipeline whole genome

项目摘要

ABSTRACT An estimated 53% of U.S. adults have dyslipidemia, putting a majority of the U.S. adult population at high risk for related chronic diseases such as cardiovascular diseases, non-alcoholic fatty liver disease, and gallbladder disease. US Hispanic/Latinos (H/L) ages 18–74 have an overall prevalence of dyslipidemia of 65%, among the highest reported in the US. Lipid traits are highly heritable; estimates range from 20 to 70%, with common genetic variants explaining ~30% of the variance for these traits in Europeans. As serum concentrations of lipids are established therapeutic targets for many lipid-related chronic diseases, researchers have invested considerable effort into understanding the genetic epidemiology of lipid traits, however these large-scale efforts have almost exclusively considered Caucasians. Understudied at-risk populations provide a powerful design to gain insight into genetic mechanisms for disease because they can exhibit finer haplotypic structure and have different underlying causal variants. To ensure ancestrally diverse populations are not the last to benefit from the new era of precision medicine, we must both increase representation of ancestrally diverse populations in genetic research and develop expedited strategies for translating genomics for clinical utility. First, to enrich discovery, we will conduct the first large-scale GWAS and rare variant analyses for lipid- related traits in H/L. We will meta-analyze, fine-map, perform multivariate associations, and validate effects in all available H/L samples in analyses that will include >50,000 samples. Second, to interpret function, we will move GWAS findings into an interpretable biological context and characterize the regulatory mechanisms involved in lipid regulation via tissue-specific functional analysis, and ancestry-specific validation of effects using RNAseq data in two independent H/L cohorts. Identification of genes and pathways associated with lipid levels elucidates important basic biology about human metabolism, but isn’t necessarily clinically translatable. Thus, to evaluate clinical significance of lipid-associated genetic risk factors, we will use multiple massive genetic and electronic medical record repositories (including the Multiethnic Cohort, BioME, and BioVU) to identify clinical outcomes associated with single variants and genetically regulated expression of lipid- associated genes in H/L phenome-wide. Our design focuses effort on discovery of new variants and loci by pioneering genetic studies of lipid-related traits in diverse H/L populations, functional interpretation of variant effects via gene-based annotation and expression prediction with robust validation, and characterizing the clinical outcomes predicted by lipid-associated genetics in three large DNA bio-banks with linked electronic medical records. These population-specific, function- and outcome-oriented approaches will advance understanding of the genetic etiology of lipids and related traits with high H/L disparities of risk, revealing new biologic pathways and providing new avenues for precision treatment for H/L, a population that will constitute ~35% of the US population by the year 2050.

抽象的据估计 53% 的美国成年人患有血脂异常，使大多数美国成年人面临高风险心血管疾病、非酒精性脂肪肝、胆囊等相关慢性疾病美国 18-74 岁西班牙裔/拉丁裔 (H/L) 人群中血脂异常的总体患病率为 65%。据报道，美国的血脂特征具有高度遗传性，估计范围为 20% 至 70%；遗传变异解释了欧洲人这些性状的约 30% 的差异。脂质是许多与脂质相关的慢性疾病的既定治疗靶标，研究人员已经投入人们为了解脂质性状的遗传流行病学付出了相当大的努力，但是这些大规模的努力几乎完全考虑了白种人，这为研究提供了强有力的设计。深入了解疾病的遗传机制，因为它们可以表现出更精细的单倍型结构并具有不同的潜在因果变异确保祖先多样化的人群不会是最后受益者。从精准医学的新时代开始，我们必须增加祖先多样化的代表性人口进行遗传研究并制定将基因组学转化为临床的快速策略首先，为了丰富发现，我们将针对脂质进行首次大规模 GWAS 和稀有变异分析。我们将对 H/L 中的相关特征进行荟萃分析、精细映射、执行多变量关联并验证效果。分析中的所有可用 H/L 样本将包括 > 50,000 个样本。其次，为了解释功能，我们将。将 GWAS 研究结果转化为可解释的生物学背景并描述调控机制通过组织特异性功能分析和祖先特异性效应验证参与脂质调节使用两个独立的 H/L 队列中的 RNAseq 数据鉴定与脂质相关的基因和途径。水平阐明了有关人类新陈代谢的重要基础生物学，但不一定可用于临床。因此，为了评估脂质相关遗传危险因素的临床意义，我们将使用多个大规模遗传和电子病历存储库（包括多种族队列、BioME 和 BioVU）确定与脂质单一变异和基因调控表达相关的临床结果我们的设计重点是发现新的变异和基因座。对不同 H/L 群体中脂质相关性状的开创性遗传学研究，变异的功能解释通过基于基因的注释和表达预测以及强大的验证来表征效果在三个大型 DNA 生物库中通过脂质相关遗传学预测临床结果这些针对特定人群、以功能和结果为导向的方法将取得进步。了解脂质的遗传病因学以及具有高 H/L 风险差异的相关特征，揭示新的生物途径并为 H/L 的精准治疗提供新途径，该人群将构成到 2050 年，约占美国人口的 35%。