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J Bone Miner Res. 2018 Jan;33(1):91-98. doi: 10.1002/jbmr.3285. Epub 2017 Oct 16.

SIRT1/HERC4 Locus Associated With Bisphosphonate-Induced Osteonecrosis of the Jaw: An Exome-Wide Association Analysis.

Author information

1
Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
2
Cancer Pharmacology Department, Levine Cancer Institute, Charlotte, NC, USA.
3
Department of Oral Medicine, College of Dentistry, University of Florida, Gainesville, FL, USA.
4
Bioinformatics Core, Interdisciplinary Center for Biotechnology Research, University of Florida, Gainesville, FL, USA.
5
1st Department of Medicine, Semmelweis University Medical School, Budapest, Hungary.
6
PentaCore Laboratory, Budapest, Hungary.
7
Department of Oro-Maxillofacial Surgery and Stomatology, Semmelweis University Dental School, Budapest, Hungary.
8
Department of Biomedical and Neuromotor Sciences, Section of Dentistry, Alma Mater Studiorum, Università di Bologna, Bologna, Italy.
9
Micromedic Technologies Ltd., Tel Aviv, Israel.
10
Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.

Abstract

Osteonecrosis of the jaw (ONJ) is a rare, but serious drug side effect, mainly associated with the use of intravenous (iv) bisphosphonates (BPs). The purpose of this study was to identify genetic variants associated with ONJ in patients of European ancestry treated with iv BPs using whole-exome sequencing (WES). The WES phase 1 included 44 multiple myeloma patients (22 ONJ cases and 22 controls) and WES phase 2 included 17 ONJ patients with solid tumors. Multivariable logistic regression analysis was performed to estimate the odds ratios (ORs) and 95% confidence intervals (CI), adjusting for age, sex, and principal components for ancestry. Meta-analysis of WES phase 1 and 2 was performed to estimate the combined ORs. In silico analyses were then performed to identify expression quantitative loci (eQTL) single-nucleotide polymorphisms (SNPs) that are in high linkage disequilibrium (LD) with the top SNPs. The associations of the potentially functional SNPs were replicated and validated in an independent case-control study of 48 patients of European ancestry treated with iv BPs (19 ONJ cases and 29 controls). The top SNPs in the exome-wide association meta-analysis were two SNPs on chromosome 10: SIRT1 SNP rs7896005 and HERC4 SNP rs3758392 with identical OR of 0.07 (0.01-0.46; p = 3.83 × 10-5 ). In the in silico functional analyses, two promoter region SNPs (rs7894483 and rs3758391) were identified to be in high LD with the index SNPs and are eQTLs for SIRT1 gene in whole blood in the GTEx database. The ORs were 0.30 (0.10-0.88), 0.26 (0.12-0.55), and 0.26 (0.12-0.55) for the WES top SNP rs7896005 and two promoter SNPs rs7894483 and rs3758391, respectively, in the replication sample. In summary, we identified the SIRT1/HERC4 locus on chromosome 10 to be associated with iv BP-induced ONJ and two promoter SNPs that might be the potential genetic markers for this association.

KEYWORDS:

BISPHOSPHONATES; OSTEONECROSIS OF THE JAW; PHARMACOGENOMICS; SIRT1 GENE; WHOLE-EXOME SEQUENCING

PMID:
28856724
DOI:
10.1002/jbmr.3285
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