An integrated genomic and lipidomic approach to human hepatic fat accumulation

描述（由申请人提供）：本研究的最终目标是利用整合基因组和脂质组学（即脂质家族）数据的系统方法，确定控制人类肝脏中各种脂质积累的遗传因素。肝脏脂肪堆积是非酒精性脂肪性肝病（NAFLD）和各种代谢并发症的标志。其机制，特别是脂肪积累的遗传基础，尚未完全阐明。这主要是由于对脂质代谢和体内平衡的复杂性了解不足。由于广泛的脂质参与脂肪积累和相关的代谢后果，因此特别有必要在系统水平上研究脂质过程。我们假设普通人群肝脏中各种脂质及其代谢物的含量是受遗传因素显著控制的数量性状；这些基因位点的发现可以为肝脏脂肪堆积及其相关疾病提供更好的认识。为了实现这一目标，我们建议使用大量肝脏组织（n=213）对脂质组进行全面的遗传定位，其中总脂肪含量已分化，并且先前已收集了全基因组基因型和转录组数据。我们将：1)对213个肝脏中的400种不同的脂质进行分析；2)开展全基因组关联研究，鉴定与肝脂质组变异相关的多态性和基因；3)在独立的肝脏样本集（n=70）中验证所发现的关联。我们期望这项研究能够确定人类肝脏脂质积累不平衡易感性的关键基因、等位基因和途径，从而为NAFLD及相关疾病的早期诊断和干预提供潜在的标志物和靶点。

DESCRIPTION (provided by applicant): The ultimate goal of this study is to identify genetic factors controlling the accumulation of various lipids in human liver, using a system approach with integrated genomic and lipidomic (i.e. lipids family) data. Hepatic fat accumulation is a hallmark of nonalcoholic fatty liver disease (NAFLD) and various metabolic complications. Its mechanism, especially the genetic basis underlying the fat accumulation, is incompletely elucidated. This is largely attributed to insufficient understanding of the complexity of lipid metabolism and homeostasis. Since a wide range of lipids are involved in fat accumulation and the associated metabolic consequences, it is particularly necessary to investigate the lipid process at the system level. We hypothesize that the contents of various lipids and their metabolites in the livers of the general population are quantitative traits significantly controlled by genetic factors; and the discovery of these genetic loci could provide better insight on the hepatic fat accumulation and associated diseases. To accomplish this, we propose to perform a comprehensive genetic mapping for lipidome using a large collection of liver tissues (n=213) in which the total fat content is differentiated, and for which genome-wide genotypic and transcriptomic data have been previously collected. We will: 1) profile >400 different lipids in each of the 213 livers; 2) perform genome-wide association study to identified polymorphisms and genes associated with variations in hepatic lipidome; and 3) validate the discovered associations in an independent liver sample set (n=70). We anticipate that this study will identify critical genes, alleles and pathways conferring susceptibility to imbalanced lipid accumulation in human liver, and will thus provide potential markers and targets for early diagnosis and intervention of NAFLD and related diseases. PUBLIC HEALTH RELEVANCE: This study will discover genes and DNA variants responsible for the accumulation of fat and fat fractions in human liver, a hallmark of nonalcoholic fatty liver disease and many other metabolic diseases, e.g. obesity and diabetes. This study will produce important information for attaining a better understanding of the development of these diseases. The study will also potentially identify molecular targets that could be used to develop better treatment.