Liver expression quantitative trait loci: a foundation for pharmacogenomic research.

Dylan M Glubb,Federico Innocenti,Neepa Dholakia

doi:10.3389/fgene.2012.00153

Dylan M Glubb, Federico Innocenti + Show 1 more

Open Access

https://doi.org/10.3389/fgene.2012.00153

Copy DOI

Abstract

Expression quantitative trait loci (eQTL) analysis can provide insights into the genetic regulation of gene expression at a genomic level and this information is proving extremely useful in many different areas of research. As a consequence of the role of the liver in drug metabolism and disposition, the study of eQTLs in primary human liver tissue could provide a foundation for pharmacogenomics. Thus far, four genome-wide eQTL studies have been performed using human livers. Many liver eQTLs have been found to be reproducible and a proportion of these may be specific to the liver. Already these data have been used to interpret and inform clinic genome-wide association studies, providing potential mechanistic evidence for clinical associations and identifying genes which may impact clinical phenotypes. However, the utility of liver eQTL data has not yet been fully explored or realized in pharmacogenomics. As further liver eQTL research is undertaken, the genetic regulation of gene expression will become much better characterized and this knowledge will create a rational basis for the prospective pharmacogenomic study of many drugs.

Highlights

As research has progressed, so has our understanding of how the genome plays a role in drug disposition and response via genes related to drug targets or absorption, distribution, metabolism, and excretion (ADME) (Goldstein et al, 2007)
The first to our knowledge to focus on liver Expression quantitative trait loci (eQTL), we aim to show that the liver eQTL knowledge could provide a foundation to clinical pharmacogenomic research
Several of these eQTL SNPs (eSNPs) are markers of pharmacogenetic associations (Table 2). These findings show that liver eQTLs may help explain the associations of single nucleotide polymorphism (SNP) with clinical phenotypes and provide a rationale for using liver eQTL data from relevant genes to select candidate SNPs for pharmacogenomic study

Summary

INTRODUCTION

Has our understanding of how the genome plays a role in drug disposition and response via genes related to drug targets or absorption, distribution, metabolism, and excretion (ADME) (Goldstein et al, 2007). LIVER eQTLS IN PHARMACOGENETIC STUDIES AND CLINICAL GENOME-WIDE ASSOCIATION STUDIES (GWAS) ADME genes with liver eQTLs, which pass multiple correction thresholds in one of the four genome-wide studies, include COMT, CYP2D6, CYP3A4, CYP3A5, MTHFR, UGT1A1, and VKORC1 (Table 2) These genes belong to a set of ‘very important pharmacogenes’ which have been identified by the PharmGKB resource Several of these eSNPs are markers of pharmacogenetic associations (Table 2) These findings show that liver eQTLs may help explain the associations of SNPs with clinical phenotypes and provide a rationale for using liver eQTL data from relevant genes to select candidate SNPs for pharmacogenomic study.

Postmortem tissue and resections from donor livers

Pharmacogenetic SNP

FUTURE DIRECTIONS

Findings

CONCLUSION