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

[11] Gender differences in drug responses [J].

Franconi, Flavia ;

Brunelleschi, Sandra ;

Steardo, Luca ;

Cuomo, Vincenzo .

PHARMACOLOGICAL RESEARCH, 2007, 55 (02) :81-95

[12]

Glubb Dylan M., 2012, Frontiers in Genetics, V3, P153, DOI 10.3389/fgene.2012.00153

[13] Mechanisms of genetic regulation in gene expression: examples from drug metabolizing enzymes and transporters [J].

Glubb, Dylan M. ;

Innocenti, Federico .

WILEY INTERDISCIPLINARY REVIEWS-SYSTEMS BIOLOGY AND MEDICINE, 2011, 3 (03) :299-313

[14] A survey of the genetics of stomach, liver, and adipose gene expression from a morbidly obese cohort [J].

Greenawalt, Danielle M. ;

Dobrin, Radu ;

Chudin, Eugene ;

Hatoum, Ida J. ;

Suver, Christine ;

Beaulaurier, John ;

Zhang, Bin ;

Castro, Victor ;

Zhu, Jun ;

Sieberts, Solveig K. ;

Wang, Susanna ;

Molony, Cliona ;

Heymsfield, Steven B. ;

Kemp, Daniel M. ;

Reitman, Marc L. ;

Lum, Pek Yee ;

Schadt, Eric E. ;

Kaplan, Lee M. .

GENOME RESEARCH, 2011, 21 (07) :1008-1016

[15] Identification, Replication, and Functional Fine-Mapping of Expression Quantitative Trait Loci in Primary Human Liver Tissue [J].

Innocenti, Federico ;

Cooper, Gregory M. ;

Stanaway, Ian B. ;

Gamazon, Eric R. ;

Smith, Joshua D. ;

Mirkov, Snezana ;

Ramirez, Jacqueline ;

Liu, Wanqing ;

Lin, Yvonne S. ;

Moloney, Cliona ;

Aldred, Shelly Force ;

Trinklein, Nathan D. ;

Schuetz, Erin ;

Nickerson, Deborah A. ;

Thummel, Ken E. ;

Rieder, Mark J. ;

Rettie, Allan E. ;

Ratain, Mark J. ;

Cox, Nancy J. ;

Brown, Christopher D. .

PLOS GENETICS, 2011, 7 (05)

[16] BinTree Seeking: A Novel Approach to Mine Both Bi-Sparse and Cohesive Modules in Protein Interaction Networks [J].

Jiao, Qing-Ju ;

Zhang, Yan-Kai ;

Li, Lu-Ning ;

Shen, Hong-Bin .

PLOS ONE, 2011, 6 (11)

[17] Inhibitory G proteins and their receptors: emerging therapeutic targets for obesity and diabetes [J].

Kimple, Michelle E. ;

Neuman, Joshua C. ;

Linnemann, Amelia K. ;

Casey, Patrick J. .

EXPERIMENTAL AND MOLECULAR MEDICINE, 2014, 46 :e102-e102

[18] Genetics of blood lipids among ∼300,000 multi-ethnic participants of the Million Veteran Program [J].

Klarin, Derek ;

Damrauer, Scott M. ;

Cho, Kelly ;

Sun, Yan, V ;

Teslovich, Tanya M. ;

Honerlaw, Jacqueline ;

Gagnon, David R. ;

Du Vall, Scott L. ;

Li, Jin ;

Peloso, Gina M. ;

Chaffin, Mark ;

Small, Aeron M. ;

Huang, Jie ;

Tang, Hua ;

Lynch, Julie A. ;

Ho, Yuk-Lam ;

Liu, Dajiangj ;

Emdin, Connor A. ;

Li, Alexander H. ;

Huffman, Jennifer E. ;

Lee, Jennifer S. ;

Natarajan, Pradeep ;

Chowdhury, Rajiv ;

Saleheen, Danish ;

Vujkovic, Ma Rijana ;

Baras, Aris ;

Pyarajan, Saiju ;

Di Angelantonio, Emanuele ;

Neale, Benjamin M. ;

Naheed, Al Iya ;

Khera, Amit, V ;

Danesh, John ;

Chan, Kyong-Mi ;

Abecasis, Goncalo ;

Willer, Cristen ;

Dewey, Frederick E. ;

Carey, David J. ;

Concato, John ;

Gaziano, J. Michael ;

O'Donnell, Christopherj ;

Tsao, Philip S. ;

Kathiresan, Sekar ;

Rader, Daniel J. ;

Wilson, Peter W. F. ;

Assimes, Themistocles L. .

NATURE GENETICS, 2018, 50 (11) :1514-+

[19] Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice [J].

Lagace, Thomas A. ;

Curtis, David E. ;

Garuti, Rita ;

McNutt, Markey C. ;

Park, Sahng Wook ;

Prather, Heidi B. ;

Anderson, Norma N. ;

Ho, Y. K. ;

Hammer, Robert E. ;

Horton, Jay D. .

JOURNAL OF CLINICAL INVESTIGATION, 2006, 116 (11) :2995-3005

[20] Genetic and Metabolic Determinants of Plasma PCSK9 Levels [J].

Lakoski, Susan G. ;

Lagace, Thomas A. ;

Cohen, Jonathan C. ;

Horton, Jay D. ;

Hobbs, Helen H. .

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2009, 94 (07) :2537-2543

← 1 2 3 4 5 →