Related Experiment Video
Updated: Oct 24, 2025
Genome-wide Mapping of Drug-DNA Interactions in Cells with COSMIC Crosslinking of Small Molecules to Isolate Chromatin
Published on: January 20, 2016
Genome-wide Association Study Identified Chromosome 8 Locus Associated with Medication-Related Osteonecrosis of the
Guang Yang1, Sonal Singh1, Caitrin W McDonough1
1Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, Florida, USA.
Abstract:
Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious drug-related adverse event. To identify pharmacogenomic markers of MRONJ associated with bisphosphonate therapy, we conducted a genomewide association study (GWAS) meta-analysis followed by functional analysis of 5,008 individuals of European ancestry treated with bisphosphonates, which includes the largest number of MRONJ cases to date (444 cases and 4,564 controls). Discovery GWAS was performed in randomly selected 70% of the patients with cancer and replication GWAS was performed in the remaining 30% of the patients with cancer treated with intravenous bisphosphonates followed by meta-analysis of all 3,639 patients with cancer. GWAS was also performed in 1,369 patients with osteoporosis treated with oral bisphosphonates. The lead single-nucleotide polymorphism (SNP), rs2736308 on chromosome 8, was associated with an increased risk of MRONJ with an odds ratio (OR) of 2.71 and 95% confidence interval (CI) of 1.90-3.86 (P = 3.57*10-8 ) in the meta-analysis of patients with cancer. This SNP was validated in the MRONJ GWAS in patients with osteoporosis (OR: 2.82, 95% CI: 1.55-4.09, P = 6.84*10-4 ). The meta-analysis combining patients with cancer and patients with osteoporosis yielded the same lead SNP rs2736308 on chromosome 8 as the top SNP (OR: 2.74, 95% CI: 2.09-3.39, P = 9.65*10-11 ). This locus is associated with regulation of the BLK, CTSB, and FDFT1 genes, which had been associated with bone mineral density. FDFT1 encodes a membrane-associated enzyme, which is implicated in the bisphosphonate pathway. This study provides insights into the potential mechanism of MRONJ.
Insights
This study identified a genetic marker, rs2736308, associated with an increased risk of medication-related osteonecrosis of the jaw (MRONJ) in patients taking bisphosphonates. This finding offers insights into MRONJ
Area of Science:
- Pharmacogenomics
- Genetics
- Oncology
- Bone Metabolism
Background:
- Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse event linked to bisphosphonate therapy.
- Identifying genetic risk factors for MRONJ is crucial for patient management and risk stratification.
Purpose of the Study:
- To identify pharmacogenomic markers associated with bisphosphonate-related MRONJ.
- To investigate the genetic underpinnings of MRONJ risk in patients treated with bisphosphonates.
Main Methods:
- A large-scale genomewide association study (GWAS) meta-analysis was conducted on 5,008 individuals of European ancestry.
- The study included patients with cancer and osteoporosis treated with bisphosphonates, analyzing 444 MRONJ cases and 4,564 controls.
- Functional analysis focused on genes near the identified single-nucleotide polymorphism (SNP).
Main Results:
- The lead SNP, rs2736308 on chromosome 8, was significantly associated with increased MRONJ risk (OR: 2.74, P=9.65*10-11).
- This SNP was consistently identified across patient cohorts (cancer and osteoporosis) and validated in independent analyses.
- The identified locus is linked to the regulation of BLK, CTSB, and FDFT1 genes, with FDFT1 implicated in the bisphosphonate pathway.
Conclusions:
- The SNP rs2736308 is a significant genetic risk factor for bisphosphonate-related MRONJ.
- These findings provide potential mechanistic insights into MRONJ development.
- This genetic marker could aid in personalized risk assessment for MRONJ.
