An international genome-wide meta-analysis of bisphosphonate related osteonecrosis of the jaw

BACKGROUND: Osteonecrosis of the jaw (ONJ), a rare but serious drug-induced adverse event, is one of the most feared and debilitating side effects of antiresorptive agents such as bisphosphonates (BPs). Despite the increasing number of ONJ cases, the patho- genesis of ONJ remains largely unknown. The objective of this study was to identify common pharmacogenomic markers that predispose patients to BP-induced ONJ using genome-wide association studies (GWAS) followed by meta-analysis. METHODS: In an international collaboration effort, imputation was per- formed on three independent GWAS cohorts and merged into total 480 cases and 107 controls. Standard quality-control procedures and principal component anal- ysis (PCA) were performed. Only genetically confirmed individuals of European descent were included in this analysis. Multivariable logistic regression analysis was performed to identify variants associated with ONJ adjusting for age, gender and PC1 and 2 using EPACTS software. Alpha level was set at 5 × 10−8 for sta- tistical significance. RESULTS: The discovery cohort included 171 multiple myeloma patients (117 cases and 54 controls) treated with intravenous BPs. A non-synonymous SNP, rs9910051 located on ATAD5 gene on chromosome 17 was associated with ONJ (P = 6.27 × 10−8, Odds ratio = 6.11, 95% confidence interval (3.17, 11.70)), and replicated in prostate cancer cohort (48 cases and 17 controls) (P = 0.00034) with a meta-analysis P=1.65×10−10. ATAD5 is implicated in DNA damage compatibility. CONCLUSION: Our data suggest that ATAD5 may be a potential candidate gene for ONJ. More validation efforts in other cancer and osteoporosis patients are ongoing. If confirmed, this finding could provide basis for treatment of pa- tients who need BPs therapy in a personalized manner.