@article{23ddaaa4f7084f849153ae6f1f637dca,
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 = "Funding Information: 1Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA; 2Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA; 3Department of Breast Oncology, MD Anderson Cancer Center, Houston, Texas, USA; 4Breast Medicine Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA; 5RIKEN Center for Integrative Medical Sciences, Yokohama City, Japan; 6Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA; 7Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, Arizona, USA; 8Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Jacksonville, Florida, USA; 9Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA. *Correspondence: Liewei Wang (wang.liewei@mayo.edu) and Richard M. Weinshilboum (weinshilboum.richard@mayo.edu) †These three authors contributed equally to this paper. Funding Information: This study was supported by National Institutes of Health (NIH) grants U19 GM61388 (the Pharmacogenomics Research Network), R01 GM28157, U54 GM114838, and R01 GM125633; the NIH/National Cancer Institute (NCI) Breast SPORE grant P50 CA116201; the Breast Cancer Research Foundation grant BCRF#39B; the Mayo Cancer Center Support grant CA 15083; and in part through the NIH/NCI Cancer Center Support Grant P30 CA008748. Funding Information: R.M.W. and L.W. are co-founders and stockholders in OneOme LLC, a pharmacogenomic decision support company. M.E.R. provides advisory or consulting to AstraZeneca, Pfizer, and McKesson, and he receives honoraria from AstraZeneca and Pfizer. He receives travel and accommodation expenses from AstraZeneca. He also receives research funding from the AstraZeneca (institution), Myriad (institution, in-kind), Invitae (institution, in-kind), Pfizer (institution), AbbVie (institution), Tesaro (institution), and Medivation. M.P.G. consults for Eli Lilly & Co and Novartis, and he receives research support from Eli Lilly & Co and Pfizer. A.M.-A. is a stockholder in Merrimack Pharmaceuticals. The other authors have no disclosure.",
year = "2019",
month = jul,
doi = "10.1002/cpt.1359",
language = "English (US)",
volume = "106",
pages = "219--227",
journal = "Clinical Pharmacology and Therapeutics",
issn = "0009-9236",
publisher = "Nature Publishing Group",
number = "1",
}