Aromatase inhibitor-associated bone fractures: A case-cohort GWAS and functional genomics

Mohan Liu, Paul E. Goss, James N. Ingle, Michiaki Kubo, Yoichi Furukawa, Anthony Batzler, Gregory D. Jenkins, Erin E. Carlson, Yusuke Nakamura, Daniel J. Schaid, Judy Anne W. Chapman, Lois E. Shepherd, Matthew J. Ellis, Sundeep Khosla, Liewei Wang, Richard M. Weinshilboum

研究成果: ジャーナルへの寄稿学術論文査読

41 被引用数 (Scopus)

抄録

Bone fractures are a major consequence of osteoporosis. There is a direct relationship between serum estrogen concentrations and osteoporosis risk. Aromatase inhibitors (AIs) greatly decrease serum estrogen levels in postmenopausal women, and increased incidence of fractures is a side effect of AI therapy. We performed a discovery case-cohort genome-wide association study (GWAS) using samples from 1071 patients, 231 cases and 840 controls, enrolled in the MA.27 breast cancer AI trial to identify genetic factors involved in AI-related fractures, followed by functional genomic validation. Association analyses identified 20 GWAS single nucleotide polymorphism (SNP) signals with P < 5E-06. After removal of signals in gene deserts and those composed entirely of imputed SNPs, we applied a functional validation “decision cascade” that resulted in validation of the CTSZ-SLMO2-ATP5E, TRAM2-TMEM14A, and MAP4K4 genes. These genes all displayed estradiol (E2)-dependent induction in human fetal osteoblasts transfected with estrogen receptor-α, and their knockdown altered the expression of known osteoporosisrelated genes. These same genes also displayed SNP-dependent variation in E2 induction that paralleled the SNP-dependent induction of known osteoporosis genes, such as osteoprotegerin. In summary, our case-cohort GWAS identified SNPs in or near CTSZ-SLMO2-ATP5E, TRAM2- TMEM14A, and MAP4K4 that were associated with risk for bone fracture in estrogen receptorpositive breast cancer patients treated with AIs. These genes displayed E2-dependent induction, their knockdown altered the expression of genes related to osteoporosis, and they displayed SNP genotype-dependent variation in E2 induction. These observations may lead to the identification of novel mechanisms associated with fracture risk in postmenopausal women treated with AIs.

本文言語英語
ページ(範囲)1740-1751
ページ数12
ジャーナルMolecular Endocrinology
28
10
DOI
出版ステータス出版済み - 01-10-2014
外部発表はい

All Science Journal Classification (ASJC) codes

  • 分子生物学
  • 内分泌学

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