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.
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.
