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

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

展开

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.

抽象的估计有53％的美国成年人患有血脂异常，使美国大多数人口高。对于相关的慢性疾病，例如心血管疾病，非酒精脂肪肝病和胆囊疾病。美国西班牙裔/拉丁裔（H/L）18-74岁的血脂异常患病率为65％，在在美国报告最高。脂质特征是高度遗传的。估计范围为20％至70％，共有遗传变异解释了欧洲人这些特征的差异的30％。作为血清浓度脂质是许多与脂质相关慢性疾病的治疗靶标，研究人员已经研究了在理解脂质特征的遗传流行病学方面的巨大努力，但是这些大规模的努力几乎完全考虑了高加索人。研究的高风险人口为洞悉疾病的遗传机制，因为它们可以提取更精细的单倍型结构并具有不同的基本因果变体。确保祖先多样化的人口不是最后一个受益的人从精密医学的新时代开始，我们都必须增加对祖先的潜水员的代表性遗传研究中的人群并制定了将基因组学转化为临床的快速策略公用事业。首先，为了丰富发现，我们将对脂质进行第一个大规模GWA和罕见的变体分析。 H/L中的相关特征。我们将进行荟萃分析，微图，进行多元关联，并验证效果分析中的所有可用的H/L样品，包括> 50,000个样品。第二，要解释功能，我们将将GWAS的发现转移到可解释的生物学环境中，并表征调节机制通过组织特异性功能分析参与脂质调节，并针对祖先的效应验证在两个独立的H/L队列中使用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代谢的重要基本生物学，但不一定在临床上可以翻译。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（包括多民族队列，BIOME和BIOVU）确定与单个变体相关的临床结果以及脂质的遗传调节表达 H/L现象中的相关基因。我们的设计重点是发现新变体和基因座的努力潜水员H/L种群中脂质相关性状的开创性遗传研究，变体的功能解释通过基于基因的注释和表达预测的效果，并通过鲁棒验证进行表征通过脂质相关遗传学预测的三个大型DNA生物银行的临床结局，具有链接的电子病历。这些特定人群，功能和面向结果的方法将推进理解脂质和相关性状的遗传病因，其风险差异很高，揭示了新的生物学途径并为H/L的精确治疗提供新的途径，该人群将构成到2050年，美国人口的35％。