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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.

clinical pharmacology and therapeutics

Anastrozole Aromatase Inhibitor Plasma Drug Concentration Genome‐Wide Association Study: Functional Epistatic Interaction Between   SLC 38A7  and   ALPPL 2