Anastrozole Aromatase Inhibitor Plasma Drug Concentration Genome-Wide Association Study: Functional Epistatic Interaction Between SLC38A7 and ALPPL2

Tanda M. Dudenkov; Duan Liu; Junmei Cairns; Sandhya Devarajan; Yongxian Zhuang; James N. Ingle; Aman U. Buzdar; Mark E. Robson; Michiaki Kubo; Anthony Batzler; Poulami Barman; Gregory D. Jenkins; Erin E. Carlson; Matthew P. Goetz; Donald W. Northfelt; Alvaro Moreno-Aspitia; Zeruesenay Desta; Joel M. Reid; Krishna R. Kalari; Liewei Wang; Richard M. Weinshilboum

doi:10.1002/cpt.1359

Anastrozole Aromatase Inhibitor Plasma Drug Concentration Genome-Wide Association Study: Functional Epistatic Interaction Between SLC38A7 and ALPPL2

Tanda M. Dudenkov, Duan Liu, Junmei Cairns, Sandhya Devarajan, Yongxian Zhuang, James N. Ingle, Aman U. Buzdar, Mark E. Robson, Michiaki Kubo, Anthony Batzler, Poulami Barman, Gregory D. Jenkins, Erin E. Carlson, Matthew P. Goetz, Donald W. Northfelt, Alvaro Moreno-Aspitia, Zeruesenay Desta, Joel M. Reid, Krishna R. Kalari, Liewei WangRichard M. Weinshilboum

Breast Medical Oncology

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

Anastrozole is a widely prescribed aromatase inhibitor for the therapy of estrogen receptor positive (ER+) breast cancer. We performed a genome-wide association study (GWAS) for plasma anastrozole concentrations in 687 postmenopausal women with ER+ breast cancer. The top single-nucleotide polymorphism (SNP) signal mapped across SLC38A7 (rs11648166, P = 2.3E-08), which we showed to encode an anastrozole influx transporter. The second most significant signal (rs28845026, P = 5.4E-08) mapped near ALPPL2 and displayed epistasis with the SLC38A7 signal. Both of these SNPs were cis expression quantitative trait loci (eQTL)s for these genes, and patients homozygous for variant genotypes for both SNPs had the highest drug concentrations, the highest SLC38A7 expression, and the lowest ALPPL2 expression. In summary, our GWAS identified a novel gene encoding an anastrozole transporter, SLC38A7, as well as epistatic interaction between SNPs in that gene and SNPs near ALPPL2 that influenced both the expression of the transporter and anastrozole plasma concentrations.

Original language	English (US)
Pages (from-to)	219-227
Number of pages	9
Journal	Clinical pharmacology and therapeutics
Volume	106
Issue number	1
DOIs	https://doi.org/10.1002/cpt.1359
State	Published - Jul 2019

ASJC Scopus subject areas

Pharmacology
Pharmacology (medical)

MD Anderson CCSG core facilities

Clinical Trials Office

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Dudenkov, T. M., Liu, D., Cairns, J., Devarajan, S., Zhuang, Y., Ingle, J. N., Buzdar, A. U., Robson, M. E., Kubo, M., Batzler, A., Barman, P., Jenkins, G. D., Carlson, E. E., Goetz, M. P., Northfelt, D. W., Moreno-Aspitia, A., Desta, Z., Reid, J. M., Kalari, K. R., ... Weinshilboum, R. M. (2019). Anastrozole Aromatase Inhibitor Plasma Drug Concentration Genome-Wide Association Study: Functional Epistatic Interaction Between SLC38A7 and ALPPL2. Clinical pharmacology and therapeutics, 106(1), 219-227. https://doi.org/10.1002/cpt.1359

Dudenkov, TM, Liu, D, Cairns, J, Devarajan, S, Zhuang, Y, Ingle, JN, Buzdar, AU, Robson, ME, Kubo, M, Batzler, A, Barman, P, Jenkins, GD, Carlson, EE, Goetz, MP, Northfelt, DW, Moreno-Aspitia, A, Desta, Z, Reid, JM, Kalari, KR, Wang, L & Weinshilboum, RM 2019, 'Anastrozole Aromatase Inhibitor Plasma Drug Concentration Genome-Wide Association Study: Functional Epistatic Interaction Between SLC38A7 and ALPPL2', Clinical pharmacology and therapeutics, vol. 106, no. 1, pp. 219-227. https://doi.org/10.1002/cpt.1359

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title = "Anastrozole Aromatase Inhibitor Plasma Drug Concentration Genome-Wide Association Study: Functional Epistatic Interaction Between SLC38A7 and ALPPL2",

abstract = "Anastrozole is a widely prescribed aromatase inhibitor for the therapy of estrogen receptor positive (ER+) breast cancer. We performed a genome-wide association study (GWAS) for plasma anastrozole concentrations in 687 postmenopausal women with ER+ breast cancer. The top single-nucleotide polymorphism (SNP) signal mapped across SLC38A7 (rs11648166, P = 2.3E-08), which we showed to encode an anastrozole influx transporter. The second most significant signal (rs28845026, P = 5.4E-08) mapped near ALPPL2 and displayed epistasis with the SLC38A7 signal. Both of these SNPs were cis expression quantitative trait loci (eQTL)s for these genes, and patients homozygous for variant genotypes for both SNPs had the highest drug concentrations, the highest SLC38A7 expression, and the lowest ALPPL2 expression. In summary, our GWAS identified a novel gene encoding an anastrozole transporter, SLC38A7, as well as epistatic interaction between SNPs in that gene and SNPs near ALPPL2 that influenced both the expression of the transporter and anastrozole plasma concentrations.",

author = "Dudenkov, {Tanda M.} and Duan Liu and Junmei Cairns and Sandhya Devarajan and Yongxian Zhuang and Ingle, {James N.} and Buzdar, {Aman U.} and Robson, {Mark E.} and Michiaki Kubo and Anthony Batzler and Poulami Barman and Jenkins, {Gregory D.} and Carlson, {Erin E.} and Goetz, {Matthew P.} and Northfelt, {Donald W.} and Alvaro Moreno-Aspitia and Zeruesenay Desta and Reid, {Joel M.} and Kalari, {Krishna R.} and Liewei Wang and Weinshilboum, {Richard M.}",

note = "Publisher Copyright: {\textcopyright} 2019 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.",

year = "2019",

month = jul,

doi = "10.1002/cpt.1359",

language = "English (US)",

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pages = "219--227",

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T1 - Anastrozole Aromatase Inhibitor Plasma Drug Concentration Genome-Wide Association Study

T2 - Functional Epistatic Interaction Between SLC38A7 and ALPPL2

AU - Dudenkov, Tanda M.

AU - Liu, Duan

AU - Cairns, Junmei

AU - Devarajan, Sandhya

AU - Zhuang, Yongxian

AU - Ingle, James N.

AU - Buzdar, Aman U.

AU - Robson, Mark E.

AU - Kubo, Michiaki

AU - Batzler, Anthony

AU - Barman, Poulami

AU - Jenkins, Gregory D.

AU - Carlson, Erin E.

AU - Goetz, Matthew P.

AU - Northfelt, Donald W.

AU - Moreno-Aspitia, Alvaro

AU - Desta, Zeruesenay

AU - Reid, Joel M.

AU - Kalari, Krishna R.

AU - Wang, Liewei

AU - Weinshilboum, Richard M.

PY - 2019/7

Y1 - 2019/7

N2 - Anastrozole is a widely prescribed aromatase inhibitor for the therapy of estrogen receptor positive (ER+) breast cancer. We performed a genome-wide association study (GWAS) for plasma anastrozole concentrations in 687 postmenopausal women with ER+ breast cancer. The top single-nucleotide polymorphism (SNP) signal mapped across SLC38A7 (rs11648166, P = 2.3E-08), which we showed to encode an anastrozole influx transporter. The second most significant signal (rs28845026, P = 5.4E-08) mapped near ALPPL2 and displayed epistasis with the SLC38A7 signal. Both of these SNPs were cis expression quantitative trait loci (eQTL)s for these genes, and patients homozygous for variant genotypes for both SNPs had the highest drug concentrations, the highest SLC38A7 expression, and the lowest ALPPL2 expression. In summary, our GWAS identified a novel gene encoding an anastrozole transporter, SLC38A7, as well as epistatic interaction between SNPs in that gene and SNPs near ALPPL2 that influenced both the expression of the transporter and anastrozole plasma concentrations.

AB - Anastrozole is a widely prescribed aromatase inhibitor for the therapy of estrogen receptor positive (ER+) breast cancer. We performed a genome-wide association study (GWAS) for plasma anastrozole concentrations in 687 postmenopausal women with ER+ breast cancer. The top single-nucleotide polymorphism (SNP) signal mapped across SLC38A7 (rs11648166, P = 2.3E-08), which we showed to encode an anastrozole influx transporter. The second most significant signal (rs28845026, P = 5.4E-08) mapped near ALPPL2 and displayed epistasis with the SLC38A7 signal. Both of these SNPs were cis expression quantitative trait loci (eQTL)s for these genes, and patients homozygous for variant genotypes for both SNPs had the highest drug concentrations, the highest SLC38A7 expression, and the lowest ALPPL2 expression. In summary, our GWAS identified a novel gene encoding an anastrozole transporter, SLC38A7, as well as epistatic interaction between SNPs in that gene and SNPs near ALPPL2 that influenced both the expression of the transporter and anastrozole plasma concentrations.

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Anastrozole Aromatase Inhibitor Plasma Drug Concentration Genome-Wide Association Study: Functional Epistatic Interaction Between SLC38A7 and ALPPL2

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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