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

Research output: Contribution to journalArticle

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 languageEnglish
Pages (from-to)219-227
Number of pages9
JournalClinical Pharmacology and Therapeutics
Volume106
Issue number1
DOIs
Publication statusPublished - 01-07-2019

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Aromatase Inhibitors
Genome-Wide Association Study
Single Nucleotide Polymorphism
Pharmaceutical Preparations
Breast Neoplasms
Quantitative Trait Loci
Estrogen Receptors
Genes
Genotype
anastrozole

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

Dudenkov, Tanda M. ; Liu, Duan ; Cairns, Junmei ; Devarajan, Sandhya ; Zhuang, Yongxian ; Ingle, James N. ; Buzdar, Aman U. ; Robson, Mark E. ; Kubo, Michiaki ; Batzler, Anthony ; Barman, Poulami ; Jenkins, Gregory D. ; Carlson, Erin E. ; Goetz, Matthew P. ; Northfelt, Donald W. ; Moreno-Aspitia, Alvaro ; Desta, Zeruesenay ; Reid, Joel M. ; Kalari, Krishna R. ; Wang, Liewei ; Weinshilboum, Richard M. / Anastrozole Aromatase Inhibitor Plasma Drug Concentration Genome-Wide Association Study : Functional Epistatic Interaction Between SLC38A7 and ALPPL2. In: Clinical Pharmacology and Therapeutics. 2019 ; Vol. 106, No. 1. pp. 219-227.
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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.",
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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

Anastrozole Aromatase Inhibitor Plasma Drug Concentration Genome-Wide Association Study : Functional Epistatic Interaction Between SLC38A7 and ALPPL2. / Dudenkov, Tanda M.; Liu, Duan; Cairns, Junmei; Devarajan, Sandhya; Zhuang, Yongxian; Ingle, James N.; Buzdar, Aman U.; Robson, Mark E.; Kubo, Michiaki; Batzler, Anthony; Barman, Poulami; Jenkins, Gregory D.; Carlson, Erin E.; Goetz, Matthew P.; Northfelt, Donald W.; Moreno-Aspitia, Alvaro; Desta, Zeruesenay; Reid, Joel M.; Kalari, Krishna R.; Wang, Liewei; Weinshilboum, Richard M.

In: Clinical Pharmacology and Therapeutics, Vol. 106, No. 1, 01.07.2019, p. 219-227.

Research output: Contribution to journalArticle

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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 - 2019/7/1

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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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