A New Liver Expression Quantitative Trait Locus Map From 1,183 Individuals Provides Evidence for Novel Expression Quantitative Trait Loci of Drug Response, Metabolic, and Sex-Biased Phenotypes

被引：23

作者：

Etheridge, Amy S. ^{[1
,2
]}

Gallins, Paul J. ^{[3
]}

Jima, Dereje ^{[3
]}

Broadaway, K. Alaine ^{[4
]}

Ratain, Mark J. ^{[5
]}

Schuetz, Erin ^{[6
]}

Schadt, Eric ^{[7
]}

Schroder, Adrian ^{[8
]}

Molony, Cliona ^{[9
]}

Zhou, Yihui ^{[3
]}

Mohlke, Karen L. ^{[4
]}

Wright, Fred A. ^{[3
]}

Innocenti, Federico ^{[1
,2
,10
]}

机构：

[1] Univ N Carolina, Eshelman Sch Pharm, Chapel Hill, NC 27515 USA

[2] Univ N Carolina, Ctr Pharmacogen & Individualized Therapy, Chapel Hill, NC 27515 USA

[3] North Carolina State Univ, Bioinformat Res Ctr, Raleigh, NC 27695 USA

[4] Univ N Carolina, Dept Genet, Chapel Hill, NC 27515 USA

[5] Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA

[6] St Jude Childrens Res Hosp, Pharmaceut Sci, 332 N Lauderdale St, Memphis, TN 38105 USA

[7] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

[8] Univ Tubingen, Ctr Bioinformat Tubingen ZBIT, Tubingen, Germany

[9] Pfizer Inc, Computat Biomed, Boston, MA USA

[10] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27515 USA

来源：

CLINICAL PHARMACOLOGY & THERAPEUTICS | 2020年 / 107卷 / 06期

基金：

美国国家卫生研究院;

关键词：

GENE-EXPRESSION; PLASMA PCSK9; TRANSCRIPTION; CHOLESTEROL; RECEPTORS; GENOMICS; DPYD;

D O I：

10.1002/cpt.1751

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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 genome-wide association study 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.

引用

页码：1383 / 1393

页数：11

共 41 条

[1] Genetic effects on gene expression across human tissues [J].

Aguet, Francois ;

Brown, Andrew A. ;

Castel, Stephane E. ;

Davis, Joe R. ;

He, Yuan ;

Jo, Brian ;

Mohammadi, Pejman ;

Park, Yoson ;

Parsana, Princy ;

Segre, Ayellet V. ;

Strober, Benjamin J. ;

Zappala, Zachary ;

Cummings, Beryl B. ;

Gelfand, Ellen T. ;

Hadley, Kane ;

Huang, Katherine H. ;

Lek, Monkol ;

Li, Xiao ;

Nedzel, Jared L. ;

Nguyen, Duyen Y. ;

Noble, Michael S. ;

Sullivan, Timothy J. ;

Tukiainen, Taru ;

MacArthur, Daniel G. ;

Getz, Gad ;

Management, Nih Program ;

Addington, Anjene ;

Guan, Ping ;

Koester, Susan ;

Little, A. Roger ;

Lockhart, Nicole C. ;

Moore, Helen M. ;

Rao, Abhi ;

Struewing, Jeffery P. ;

Volpi, Simona ;

Collection, Biospecimen ;

Brigham, Lori E. ;

Hasz, Richard ;

Hunter, Marcus ;

Johns, Christopher ;

Johnson, Mark ;

Kopen, Gene ;

Leinweber, William F. ;

Lonsdale, John T. ;

McDonald, Alisa ;

Mestichelli, Bernadette ;

Myer, Kevin ;

Roe, Bryan ;

Salvatore, Michael ;

Shad, Saboor .

NATURE, 2017, 550 (7675) :204-+

[2] Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update [J].

Amstutz, Ursula ;

Henricks, Linda M. ;

Offer, Steven M. ;

Barbarino, Julia ;

Schellens, Jan H. M. ;

Swen, Jesse J. ;

Klein, Teri E. ;

McLeod, Howard L. ;

Caudle, Kelly E. ;

Diasio, Robert B. ;

Schwab, Matthias .

CLINICAL PHARMACOLOGY & THERAPEUTICS, 2018, 103 (02) :210-216

[3] Activating transcription factor 3 is a novel repressor of the nuclear factor erythroid-derived 2-related factor 2 (Nrf2)-regulated stress pathway [J].

Brown, Stephan L. ;

Sekhar, Konjeti R. ;

Rachakonda, Girish ;

Sasi, Soumya ;

Freeman, Michael L. .

CANCER RESEARCH, 2008, 68 (02) :364-368

[4]

Chaudhary R, 2017, WORLD J CARDIOL, V9, P76, DOI 10.4330/wjc.v9.i2.76

[5]

Chhibber A, 2014, PHARMACOGENOMICS, V15, P2025, DOI [10.2217/pgs.14.144, 10.2217/PGS.14.144]

[6] Role of activating transcription factor 3 in fructose-induced metabolic syndrome in mice [J].

Chou, Chu-Lin ;

Li, Ching-Hao ;

Lin, Heng ;

Liao, Mei-Hui ;

Wu, Chin-Chen ;

Chen, Jin-Shuen ;

Sue, Yuh-Mou ;

Fang, Te-Chao .

HYPERTENSION RESEARCH, 2018, 41 (08) :589-597

[7] Genome-Wide Association Study Evaluating Lipoprotein-Associated Phospholipase A2 Mass and Activity at Baseline and After Rosuvastatin Therapy [J].

Chu, Audrey Y. ;

Guilianini, Franco ;

Grallert, Harald ;

Dupuis, Josee ;

Ballantyne, Christie M. ;

Barratt, Bryan J. ;

Nyberg, Fredrik ;

Chasman, Daniel I. ;

Ridker, Paul M. .

CIRCULATION-CARDIOVASCULAR GENETICS, 2012, 5 (06) :676-685

[8] Androgen receptor-mediated antagonism of estrogen-dependent low density lipoprotein receptor transcription in cultured hepatocytes [J].

Croston, GE ;

Milan, LB ;

Marschke, KB ;

Reichman, M ;

Briggs, MR .

ENDOCRINOLOGY, 1997, 138 (09) :3779-3786

[9] Sex-biased genetic effects on gene regulation in humans [J].

Dimas, Antigone S. ;

Nica, Alexandra C. ;

Montgomery, Stephen B. ;

Stranger, Barbara E. ;

Raj, Towfique ;

Buil, Alfonso ;

Giger, Thomas ;

Lappalainen, Tuuli ;

Gutierrez-Arcelus, Maria ;

McCarthy, Mark I. ;

Dermitzakis, Emmanouil T. .

GENOME RESEARCH, 2012, 22 (12) :2368-2375

[10]

Endocrinologic and Metabolic Drugs Advisory Committee, 2015, FDA ADV COMM BRIEF D

← 1 2 3 4 5 →