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Anastrozole Aromatase Inhibitor Plasma Drug Concentration Genome‐Wide Association Study: Functional Epistatic Interaction Between SLC 38A7 and ALPPL 2
Author(s) -
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.,
MorenoAspitia Alvaro,
Desta Zeruesenay,
Reid Joel M.,
Kalari Krishna R.,
Wang Liewei,
Weinshilboum Richard M.
Publication year - 2019
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.1359
Subject(s) - anastrozole , snp , single nucleotide polymorphism , genome wide association study , aromatase , aromatase inhibitor , epistasis , biology , estrogen receptor , genotype , expression quantitative trait loci , breast cancer , genetics , medicine , gene , cancer
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 SLC 38A7 (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 ALPPL 2 and displayed epistasis with the SLC 38A7 signal. Both of these SNP s were cis expression quantitative trait loci ( eQTL )s for these genes, and patients homozygous for variant genotypes for both SNP s had the highest drug concentrations, the highest SLC 38A7 expression, and the lowest ALPPL 2 expression. In summary, our GWAS identified a novel gene encoding an anastrozole transporter, SLC 38A7 , as well as epistatic interaction between SNP s in that gene and SNP s near ALPPL 2 that influenced both the expression of the transporter and anastrozole plasma concentrations.