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阿那曲唑芳香酶抑制剂血浆药物浓度全基因组关联研究：SLC38A7 和 ALPPL2 之间的功能上位性相互作用。

Anastrozole Aromatase Inhibitor Plasma Drug Concentration Genome-Wide Association Study: Functional Epistatic Interaction Between SLC38A7 and ALPPL2.

机构信息

Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.

Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA.

出版信息

Clin Pharmacol Ther. 2019 Jul;106(1):219-227. doi: 10.1002/cpt.1359. Epub 2019 Mar 18.

DOI:10.1002/cpt.1359
PMID:30648747
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6612579/
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.

摘要

阿那曲唑是一种广泛应用于治疗雌激素受体阳性（ER+）乳腺癌的芳香化酶抑制剂。我们对 687 名接受阿那曲唑治疗的绝经后 ER+乳腺癌患者的血浆阿那曲唑浓度进行了全基因组关联研究（GWAS）。位于 SLC38A7 上的单核苷酸多态性（SNP）信号最为显著（rs11648166，P=2.3E-08），该 SNP 编码阿那曲唑摄取转运体。第二个最显著的信号（rs28845026，P=5.4E-08）位于 ALPPL2 附近，与 SLC38A7 信号存在上位性。这两个 SNP 都是这两个基因的顺式表达数量性状基因座（cis-eQTL），两种 SNP 变异基因型纯合的患者药物浓度最高，SLC38A7 表达最高，ALPPL2 表达最低。总之，我们的 GWAS 鉴定了一个新的基因，该基因编码阿那曲唑转运体 SLC38A7，以及该基因中的 SNP 与 ALPPL2 附近 SNP 之间的上位性相互作用，影响转运体的表达和阿那曲唑的血浆浓度。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f39/6617979/5f1822c8c634/CPT-106-219-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f39/6617979/0866c94e00d8/CPT-106-219-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f39/6617979/37d58239e795/CPT-106-219-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f39/6617979/d51ad27f8ffb/CPT-106-219-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f39/6617979/7e2047e9c5b4/CPT-106-219-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f39/6617979/346eff7d28af/CPT-106-219-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f39/6617979/5f1822c8c634/CPT-106-219-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f39/6617979/0866c94e00d8/CPT-106-219-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f39/6617979/37d58239e795/CPT-106-219-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f39/6617979/d51ad27f8ffb/CPT-106-219-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f39/6617979/7e2047e9c5b4/CPT-106-219-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f39/6617979/346eff7d28af/CPT-106-219-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f39/6617979/5f1822c8c634/CPT-106-219-g006.jpg

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