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

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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.

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

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

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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