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Clin Pharmacol Ther. 2019 Dec 23. doi: 10.1002/cpt.1751. [Epub ahead of print]

A new liver eQTL map from 1,183 individuals provides evidence for novel eQTLs of drug response, metabolic and sex-biased phenotypes.

Author information

1
Eshelman School of Pharmacy and Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, 120 Mason Farm Road, Chapel Hill, NC, USA, 27599.
2
Bioinformatics Research Center, North Carolina State University, 1 Lampe Drive, Raleigh, NC, USA, 27695.
3
Department of Genetics, University of North Carolina at Chapel Hill, 120 Mason Farm Road, Chapel Hill, NC, USA, 27599.
4
Department of Medicine, The University of Chicago, 5841 South Maryland Avenue, MC 2115, Chicago, IL, USA.
5
Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, USA, 38105.
6
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY, USA, 10029.
7
Center for Bioinformatics Tübingen (ZBIT), University of Tübingen, Sand 1, 72076, Tübingen, Germany.
8
Computation Biomedicine, Pfizer, Inc., Boston, MA.
9
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 120 Mason Farm Road, Chapel Hill, NC, USA, 27599.

Abstract

Expression quantitative trait locus (eQTL) studies in human liver are crucial for elucidating how genetic variation influences variability in disease risk and therapeutic outcomes and may help guide strategies to obtain maximal efficacy and safety of clinical interventions. Associations between expression microarray and genome-wide genotype data from four human liver eQTL studies (n=1,183) were analyzed. More than 2.3 million cis-eQTLs for 15,668 genes were identified. When eQTLs were filtered against a list of 1,496 drug response genes, 187,829 cis-eQTLs for 1,191 genes were identified. Additionally, 1,683 sex-biased cis-eQTLs were identified, as well as 49 and 73 cis-eQTLs that colocalized with GWAS signals for blood metabolite or lipid levels, respectively. Translational relevance of these results is evidenced by linking DPYD eQTLs to differences in safety of chemotherapy, linking the sex-biased regulation of PCSK9 expression to anti-lipid therapy, and identifying the G-protein coupled receptor GPR180 as a novel drug target for hypertriglyceridemia.

KEYWORDS:

drug response; eQTL; liver; metabolism; sex

PMID:
31868224
DOI:
10.1002/cpt.1751

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