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Genomics of ADME gene expression: mapping expression quantitative trait loci relevant for absorption, distribution, metabolism and excretion of drugs in human liver

Abstract:

Expression quantitative trait loci (eQTL) analysis is a powerful approach toward identifying genetic loci associated with quantitative changes in gene expression. We applied genome-wide association analysis to a data set of >300 000 single-nucleotide polymorphisms and >48 000 mRNA expression phenotypes obtained by Illumina microarray profiling of 149 human surgical liver samples obtained from Caucasian donors with detailed medical documentation. Of 1226 significant associations, only 200 were validated when comparing with a previously published similar study. Potential explanations for low replication rate include differences in microarray platforms, statistical modeling, covariates considered and origin and collection procedures of tissues. Focused analysis revealed a subset of 95 associations related to absorption, distribution, metabolism and excretion of drugs. Of these, 21 were true replications and 74 were newly discovered associations in enzymes, transporters, transcriptional regulators and other genes. This study extends our knowledge about the genetics of inter-individual variability of gene expression with particular emphasis on pharmacogenomics.The Pharmacogenomics Journal advance online publication, 18 October 2011; doi:10.1038/tpj.2011.44.

22006096

Projects: A1.2: Detoxification in hepatocytes challenged by steatotic conditions, A3.4: Linking signalling to metabolic functions, B5: Cell-cell communication influences detoxifying functions in hepatocytes, C3: Zonation of metabolism and its regulation, G1: Clinical Translation to Invasively Characterized Patients, G2: Clinical Translation to Non-Invasive Volunteer Setting, G3: Clinical Translation to Pharmaceutical Drug Development, G4: Whole-Body Detoxification in Mouse Models


Pharmacogenomics J. 13(1): 12-20
18th Oct 2011

A Schröder, K Klein, S Winter, M Schwab, M Bonin, A Zell, U M Zanger

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[Adrian Schröder] [Kathrin Klein] [Matthias Schwab] [Andreas Zell] [Ulrich Zanger]
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Views: 2500
  • Created: 3rd Nov 2011 at 10:45
  • Last updated: 24th Oct 2013 at 16:17

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