Genome-wide Association Study Identified Chromosome 8 Locus Associated with Medication-Related Osteonecrosis of the Jaw.

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.

• Authors: Guang Yang, Sonal Singh, Caitrin W McDonough, Jatinder K Lamba, Issam Hamadeh, L Shannon Holliday, Danxin Wang, Joseph Katz, Peter A Lakatos, Bernadett Balla, Janos P Kosa, Gian Andrea Pelliccioni, Douglas K Price, Sara L Van Driest, William D Figg, Taimour Langaee, Jan S Moreb, Yan Gong
• Journal: Clinical pharmacology and therapeutics (Clin Pharmacol Ther) Vol. 110 Issue 6 Pg. 1558-1569 (12 2021) ISSN: 1532-6535 [Electronic] United States
• PMID: 34390503 (Publication Type: Journal Article, Meta-Analysis, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Chemical References

• Diphosphonates

Topics

• Bisphosphonate-Associated Osteonecrosis of the Jaw (diagnosis, genetics)
• Case-Control Studies
• Chromosomes, Human, Pair 8 (genetics)
• Diphosphonates (adverse effects, therapeutic use)
• Genetic Loci (genetics)
• Genome-Wide Association Study (methods)
• Humans
• Neoplasms (drug therapy, genetics)
• Osteoporosis (drug therapy, genetics)
• Polymorphism, Single Nucleotide (genetics)