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 language | English (US) |
|---|---|
| Journal | Clinical pharmacology and therapeutics |
| DOIs | |
| State | Published - Jan 1 2019 |
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ASJC Scopus subject areas
- Pharmacology
- Pharmacology (medical)
Cite this
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 Philip; Northfelt, Donald W; Moreno Aspitia, Alvaro; Desta, Zeruesenay; Reid, Joel M; Kalari, Krishna R; Wang, Liewei M; Weinshilboum, Richard M.
In: Clinical pharmacology and therapeutics, 01.01.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Anastrozole Aromatase Inhibitor Plasma Drug Concentration Genome-Wide Association Study
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 Philip
AU - Northfelt, Donald W
AU - Moreno Aspitia, Alvaro
AU - Desta, Zeruesenay
AU - Reid, Joel M
AU - Kalari, Krishna R
AU - Wang, Liewei M
AU - Weinshilboum, Richard M
PY - 2019/1/1
Y1 - 2019/1/1
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.
UR - http://www.scopus.com/inward/record.url?scp=85062937190&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85062937190&partnerID=8YFLogxK
U2 - 10.1002/cpt.1359
DO - 10.1002/cpt.1359
M3 - Article
C2 - 30648747
AN - SCOPUS:85062937190
JO - Clinical Pharmacology and Therapeutics
JF - Clinical Pharmacology and Therapeutics
SN - 0009-9236
ER -