Hispanic Latino Lipid Consortium

摘要 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处于高风险之中。 用于相关慢性疾病，如心血管疾病、非酒精性脂肪肝和胆囊 疾病美国18-74岁的西班牙裔/拉丁裔（H/L）血脂异常的总体患病率为65%， 最高的报告在美国。脂质性状是高度遗传的;估计范围从20至70%，与常见的 遗传变异解释了欧洲人这些特征变异的30%。由于血清中 脂质是许多脂质相关慢性疾病的既定治疗靶点， 相当大的努力来了解脂质性状的遗传流行病学，然而，这些大规模的努力 几乎只考虑白种人未充分研究的高危人群提供了一个强大的设计， 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， 不同的潜在因果变量。确保祖先多样化的人口不是最后受益者 从精准医疗的新时代开始，我们必须增加祖先多样性的代表性， 在遗传研究中的人口，并制定加快战略，将基因组学用于临床 效用首先，为了丰富发现，我们将进行第一次大规模的GWAS和罕见的脂质变异分析， H/L相关性状我们将进行荟萃分析，精细映射，执行多变量关联，并验证 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的发现转移到可解释的生物学背景中，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RNAseq数据在两个独立的H/L群组中。与脂质相关的基因和途径的鉴定 水平阐明了关于人体代谢的重要基础生物学，但不一定是临床上可翻译的。 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的 基因和电子病历库（包括多种族队列、BioME和BioVU）， 确定与单个变异和脂质基因调控表达相关的临床结局， H/L全表型相关基因。我们的设计集中在发现新的变异和基因座的努力， 在不同的H/L人群中开创性的脂质相关性状的遗传研究，变异的功能解释， 通过基于基因的注释和具有稳健验证的表达预测， 在三个大型DNA生物库中通过脂质相关遗传学预测的临床结局， 医疗记录这些针对具体人群、注重职能和成果的办法将得到推进 了解高H/L风险差异的脂质和相关性状的遗传病因，揭示了新的 生物途径，并为H/L的精确治疗提供新的途径，这一人群将构成 到2050年将占美国人口的35%。

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.