Genome-wide SNP genotyping and expression analysis in human livers

人类肝脏全基因组 SNP 基因分型和表达分析

• 批准号: 7808084
• 负责人: FEDERICO INNOCENTI
• 金额: $ 19.31万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7808084
• 关键词: Amino Acids; Bile Acids; Biological Assay; Caucasians; Caucasoid Race; Chromosomes; Collection; Complex; Copy Number Polymorphism; DNA; Diabetes Mellitus; Distant; Ensure; Functional RNA; Gene Deletion; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Variation; Genome; Genomics; Genotype; Goals; Hepatic; Hepatocyte; Human; Individual; Investigation; Linkage Disequilibrium; Liver; Liver diseases; Measures; Metabolism; Molecular Profiling; Non-Insulin-Dependent Diabetes Mellitus; Pattern; Pharmaceutical Preparations; Pharmacogenetics; Phase; Phenotype; Physiological; Plasma Proteins; Play; Protein Biosynthesis; Quantitative Trait Loci; RNA; Relative (related person); Research Design; Role; Sampling; Scanning; Single Nucleotide Polymorphism; Techniques; Technology; Therapeutic Intervention; Time; Tissues; Trans-Activators; Variant; Xenobiotics; base; carbohydrate metabolism; drug metabolism; genome wide association study; genome-wide; glucose metabolism; human tissue; interest; lipid metabolism; liver function; mRNA Expression; novel; public health relevance; response; trait

DESCRIPTION (provided by applicant): The large number of hepatocytes in the liver fulfills multiple functions, including plasma protein synthesis, carbohydrate metabolism, amino acid metabolism, lipid metabolism, drug metabolism, and bile acid secretion. In a few studies conducted previously in a small number of livers, high inter-individual variability in gene expression has been observed. The underlying genetic factors responsible for such differences in expression among individuals are likely to be several, for example, duplications and deletions of genes, single nucleotide polymorphisms (SNPs), copy number variations (CNVs) and others. The investigation of the relative contributions of each of these factors to the expression profile of a tissue was seen as a daunting challenge. The recent availability of high-throughput SNP platforms allows the interrogation of hundreds of thousands of SNPs in an individual. In addition, they also provide the assessment of the CNV pattern in the genome. Hence, in this project, we will assess the pattern of genome wide mRNA expression and genetic variation in 220 normal human livers from Caucasian donors. The overall goal of this proposal is to obtain, for the first time, the genomic signature of the regulation of gene expression in the human liver. DNA and RNA samples are already extracted and are in a sufficient amount for genome wide SNP and expression analysis. The genome wide SNP scan of DNA will be performed by using the Affymetrix Human SNP Array 6.0. mRNA expression will be measured by using the GeneChip(R) Human Gene 1.0 ST Array. Using standard and novel statistical techniques, we will identify and characterize cis- and trans-acting eQTLs and the regulatory networks of gene expression in the human liver. The identification of these genetic regulators of mRNA expression is of high interest, as they are likely to play critical roles in liver function, liver disease, diabetes, and variability in drug response. They may represent novel targets for therapeutic intervention. PUBLIC HEALTH RELEVANCE: The aim of this study is to discover the relationships existing between patterns of genomic DNA variation and inter-individual variability in gene expression in the liver. The identification of the genetic regulators of mRNA expression in the human liver has important implications, as these genetic regulators are likely to play critical roles in liver function, liver disease and diabetes, and may represent novel targets for therapeutic intervention.

描述（由申请方提供）：肝脏中的大量肝细胞具有多种功能，包括血浆蛋白合成、碳水化合物代谢、氨基酸代谢、脂质代谢、药物代谢和胆汁酸分泌。在以前在少数肝脏中进行的一些研究中，观察到基因表达的个体间差异很大。导致个体间表达差异的潜在遗传因素可能有几种，例如基因的重复和缺失、单核苷酸多态性（SNP）、拷贝数变异（CNV）等。研究这些因素中的每一个对组织表达谱的相对贡献被视为一个艰巨的挑战。高通量SNP平台的最近可用性允许个体中数十万个SNP的询问。此外，它们还提供了基因组中CNV模式的评估。因此，在本项目中，我们将评估220例来自高加索供体的正常人类肝脏的全基因组mRNA表达和遗传变异模式。该提案的总体目标是首次获得人类肝脏中基因表达调控的基因组特征。DNA和RNA样品已经被提取，并且具有足够的量用于全基因组SNP和表达分析。将使用Affyscore Human SNP Array 6.0进行DNA的全基因组SNP扫描。将使用GeneChip（R）Human Gene 1.0 ST Array测量mRNA表达。使用标准和新的统计技术，我们将确定和表征顺式和反式作用的eQTL和人类肝脏基因表达的调控网络。这些mRNA表达的遗传调节因子的鉴定具有很高的意义，因为它们可能在肝功能、肝病、糖尿病和药物反应的变异性中发挥关键作用。它们可能是治疗干预的新靶点。公共卫生关系：本研究的目的是发现基因组DNA变异模式与肝脏基因表达个体间变异之间的关系。人类肝脏中mRNA表达的遗传调节因子的鉴定具有重要意义，因为这些遗传调节因子可能在肝功能、肝病和糖尿病中起关键作用，并且可能代表治疗干预的新靶点。