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Pharmacogenomics of osteonecrosis of the jaw
Guang Yang1, Sonal Singh1, Yiqing Chen1
1Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, FL, USA.
Abstract:
Osteonecrosis of the jaw (ONJ) is a rare but serious drug induced adverse event, mainly associated with the use of antiresorptive medications, such as intravenous (IV) bisphosphonates (BPs) in cancer patients. In this review, we evaluated all the pharmacogenomic association studies for ONJ published up to December 2018. To date, two SNPs (CYP2C8 rs1934951 and RBMS3 rs17024608) were identified to be associated with ONJ by two genome-wide association studies (GWAS). However, all six subsequent candidate gene studies failed to replicate these results. In addition, six discovery candidate gene studies tried to identify the genetic markers in several genes associated with bone remodeling, bone mineral density, or osteoporosis. After evaluating the results of these 6 studies, none of the SNPs was significantly associated with ONJ. Recently, two whole-exome sequencing (WES) analysis (including one from our group) were performed to identify variants associated with ONJ. So far, only our study successfully replicated discovery result indicating SIRT1 SNP rs7896005 to be associated with ONJ. However, this SNP also did not reach genome-wide significance. The major limitations of these studies include lack of replication phases and limited sample sizes. Even though some studies had larger sample sizes, they recruited healthy individuals as controls, not subjects treated with BPs. We conclude that a GWAS with a larger sample size followed by replication phase will be needed to fully investigate the pharmacogenomic markers of ONJ.
Insights
Pharmacogenomic studies for osteonecrosis of the jaw (ONJ) have yielded inconsistent results. Larger genome-wide association studies (GWAS) with replication phases are needed to identify reliable genetic markers for ONJ risk.
Area of Science:
- Pharmacogenomics
- Genetics of Adverse Drug Reactions
- Oncology Supportive Care
Background:
- Osteonecrosis of the jaw (ONJ) is a severe adverse event linked to antiresorptive drugs, particularly bisphosphonates (BPs), in cancer patients.
- Understanding the genetic factors influencing ONJ risk is crucial for personalized treatment strategies.
Purpose of the Study:
- To review and evaluate pharmacogenomic association studies for osteonecrosis of the jaw (ONJ) published up to December 2018.
- To identify genetic markers associated with ONJ susceptibility in patients treated with antiresorptive medications.
Main Methods:
- Systematic review of published pharmacogenomic association studies for ONJ.
- Evaluation of genome-wide association studies (GWAS), candidate gene studies, and whole-exome sequencing (WES) analyses.
- Analysis of single nucleotide polymorphisms (SNPs) and genetic variants associated with ONJ.
Main Results:
- Initial GWAS identified two SNPs (CYP2C8 rs1934951, RBMS3 rs17024608), but subsequent replication studies failed.
- Candidate gene studies and WES analyses have not consistently identified significant genetic markers for ONJ.
- One study reported a potential association with SIRT1 SNP rs7896005, but it lacked genome-wide significance and replication.
Conclusions:
- Current pharmacogenomic research for ONJ is limited by small sample sizes and a lack of robust replication phases.
- Control groups in some studies included healthy individuals, not patients treated with bisphosphonates, potentially confounding results.
- Larger-scale GWAS followed by rigorous replication are essential to identify reliable pharmacogenomic markers for ONJ.
