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Anastrozole Aromatase Inhibitor Plasma Drug Concentration Genome-Wide Association Study: Functional Epistatic
Tanda M Dudenkov1, Duan Liu1, Junmei Cairns1
1Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
Clinical Pharmacology and Therapeutics
|January 17, 2019
Summary
A genome-wide association study identified SLC38A7 as a novel gene encoding an anastrozole transporter. This study also revealed an epistatic interaction influencing drug concentrations in breast cancer patients.
Area of Science:
- Pharmacogenomics
- Oncology
- Genetics
Background:
- Anastrozole is a key aromatase inhibitor for estrogen receptor-positive (ER+) breast cancer treatment.
- Understanding factors influencing anastrozole plasma concentrations is crucial for optimizing therapy.
Purpose of the Study:
- To identify genetic factors influencing plasma anastrozole concentrations using a genome-wide association study (GWAS).
- To investigate the functional role of identified genetic variants in anastrozole transport and metabolism.
Main Methods:
- Conducted a GWAS in 687 postmenopausal women with ER+ breast cancer to analyze plasma anastrozole levels.
- Utilized SNP analysis, gene expression data (eQTLs), and investigated gene-gene interactions (epistasis).
Main Results:
- Identified a significant association between single-nucleotide polymorphisms (SNPs) in SLC38A7 (rs11648166) and anastrozole concentrations.
- Discovered a second significant SNP (rs28845026) near ALPPL2, showing epistatic interaction with the SLC38A7 SNP.
- Demonstrated that SLC38A7 encodes an anastrozole influx transporter.
- Found that homozygous variant genotypes for both SNPs correlated with highest drug levels, highest SLC38A7 expression, and lowest ALPPL2 expression.
Conclusions:
- The GWAS successfully identified SLC38A7 as a novel gene encoding an anastrozole transporter.
- An epistatic interaction between SLC38A7 and ALPPL2 genetic variants influences anastrozole transporter expression and plasma concentrations.
- These findings provide critical insights into the pharmacogenomics of anastrozole therapy for breast cancer.
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