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

ABSTRACT

UNLABELLED Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a serious adverse drug reaction. We conducted 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 develop 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.