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Mol Endocrinol. 2014 Oct;28(10):1740-51. doi: 10.1210/me.2014-1147. Epub 2014 Aug 22.

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

Author information

1
Division of Clinical Pharmacology (M.L., L.W., R.M.W.), Department of Molecular Pharmacology and Experimental Therapeutics; Departments of Oncology (J.N.I.) and Health Sciences Research (A.B., G.D.J., E.E.C., D.J.S.); and Division of Endocrinology (S.K.), Mayo Clinic, Rochester, Minnesota 55905; Massachusetts General Hospital (P.E.G.), Harvard University, Boston, Massachusetts 02114; Rikagaku Kenkyūsho Center for Integrative Medical Science (M.K., Y.F.), Yokohama, Japan 230-0045; School of Medicine (Y.N.), Chicago University, Chicago, Illinois 60637; National Cancer Institute of Canada Clinical Trials Group (J.-A.W.C., L.E.S.), Kingston, Ontario, Canada K7L 3N6; and Division of Oncology (M.J.E.), Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110.

Abstract

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 osteoporosis-related 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 receptor-positive 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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00283608.

PMID:
25148458
PMCID:
PMC4179631
DOI:
10.1210/me.2014-1147
[Indexed for MEDLINE]
Free PMC Article

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