An integrated genomic and lipidomic approach to human hepatic fat accumulation

描述(由申请人提供)：这项研究的最终目标是使用系统方法，结合基因组和脂类(即脂类家族)数据，识别控制人类肝脏中各种脂类积累的遗传因素。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。其发病机制，尤其是脂肪堆积的遗传基础尚未完全阐明。这在很大程度上归因于对脂代谢和动态平衡的复杂性认识不足。由于脂肪堆积和相关的代谢后果涉及广泛的脂类，因此在系统水平上研究脂类的过程尤为必要。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着控制的数量性状，这些遗传位点的发现可以更好地了解肝脏脂肪堆积和相关疾病。为了实现这一点，我们建议使用大量的肝组织(n=213)进行全面的基因定位，这些组织中的总脂肪含量是不同的，并且以前已经收集了全基因组的基因型和转录组数据。我们将：1)分析213个肝脏中的400种不同的脂质；2)进行全基因组范围的关联研究，以确定与肝脂多态和变异相关的基因；以及3)在一个独立的肝脏样本集中验证已发现的关联(n=70)。我们期望这项研究将发现人类肝脏对不平衡脂肪堆积的易感性的关键基因、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。 与公共健康相关：这项研究将发现导致人类肝脏脂肪和脂肪部分积累的基因和DNA变体，这是非酒精性脂肪性肝病和许多其他代谢性疾病的标志，如肥胖和糖尿病。这项研究将为更好地了解这些疾病的发展提供重要信息。这项研究还可能确定可用于开发更好治疗方法的分子靶点。

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.