Genomewide pharmacogenetics of bisphosphonate-induced osteonecrosis of the jaw: The role of RBMS3

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a serious adverse drug reaction.Weconducted a genomewide association study to search for genetic variants with a large effect size that increase the risk for BRONJ. Methods. We ascertained BRONJ cases according to the diagnostic criteria of the American Association of Oral and Maxillofacial Surgeons. We genotyped cases and a set of treatment-matched controls using Illumina Human Omni Express 12v1 chip (733,202 markers). To maximize the power of the study, we expanded the initial control set by including population and treatment-tolerant controls from publicly available sources. Imputation at the whole-genome level was performed to increase the number of single nucleotide polymorphisms (SNPs) investigated. Tests of association were carried out by logistic regression, adjusting for population structure. We also examined a list of candidate genes comprising genes potentially involved in the pathogenesis of BRONJ and genes related to drug absorption, distribution, metabolism, and excretion. Results. Based on principal component analysis, we initially analyzed 30 white cases and 17 treatment-tolerant controls. We subsequently expanded the control set to include 60 genetically matched controls per case. Association testing identified a significant marker in the RBMS3 gene, rs17024608 (p-value < 7 × 10-8); individuals positive for the SNP were 5.8× more likely to de- velop BRONJ (odds ratio, 5.8; 95% confidence interval, 3.1-11.1). Candidate gene analysis further identified SNPs in IGFBP7 and ABCC4 as potentially implicated in BRONJ risk. Conclusion. Our findings suggest that genetic susceptibility plays a role in the pathophysiology of BRONJ, with RBMS3 having a significant effect in the risk.