Genomewide Pharmacogenetics of Bisphosphonate-Induced Osteonecrosis of the Jaw: The Role of RBMS3

Center for Computational Biology and Bioinformatics, Columbia University Medical Center, New York, New York 10032, USA.
The Oncologist (Impact Factor: 4.87). 02/2012; 17(2):279-87. DOI: 10.1634/theoncologist.2011-0202
Source: PubMed


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.
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.
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.
Our findings suggest that genetic susceptibility plays a role in the pathophysiology of BRONJ, with RBMS3 having a significant effect in the risk.

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    • "Single nucleotide polymorphisms in the cytochrome P450-2C gene and IGF 1 genes may play part in the pathogenesis of BRONJ [30, 31]. "
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    ABSTRACT: Oral bisphosphonates are the most commonly prescribed antiresorptive drugs for the treatment of osteoporosis. However, there are several adverse effects associated with oral bisphosphonates including the bisphosphonate related osteonecrosis of the jaw (BRONJ). With a better understanding of this side effect, reported incidences for BRONJ in oral bisphosphonate users have increased in time. The pathogenesis of BRONJ has not been well determined. Several risk factors such as dentoalveolar surgery, therapy duration, and concomitant steroid usage have been linked to BRONJ. Conservative and surgical methods can be preferred in the treatment. Preventative measures are of great importance for the patients at high risk. In this paper, osteonecrosis of the jaw secondary to oral bisphosphonates was reviewed in order to increase awareness as well as to renew the current knowledge.
    Full-text · Article · May 2013
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    • "In addition to the adverse drug reactions discussed in detail in this article, there are a number of other relatively common reactions, including clozapine-induced agranulocytosis, bisphosphonate-induced osteonecrosis of the jaw (BONJ) and renal toxicity, that are important clinical problems. Clozapine-induced agranulocytosis has recently been shown to be HLA-associated [90] and some genetic risk factors for BONJ [91,92] have also been described. Genetic aspects of drug-induced renal toxicity are still poorly understood despite being a common form of adverse drug reaction and also a cause of drug attrition, so further studies in this area would be valuable. "
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    ABSTRACT: Considerable progress has been made in identifying genetic risk factors for idiosyncratic adverse drug reactions in the past 30 years. These reactions can affect various tissues and organs, including liver, skin, muscle and heart, in a drug-dependent manner. Using both candidate gene and genome-wide association studies, various genes that make contributions of varying extents to each of these forms of reactions have been identified. Many of the associations identified for reactions affecting the liver and skin involve human leukocyte antigen (HLA) genes and for reactions relating to the drugs abacavir and carbamazepine, HLA genotyping is now in routine use prior to drug prescription. Other HLA associations are not sufficiently specific for translation but are still of interest in relation to underlying mechanisms for the reactions. Progress on non-HLA genes affecting adverse drug reactions has been less, but some important associations, such as those of SLCO1B1 and statin myopathy, KCNE1 and drug-induced QT prolongation and NAT2 and isoniazid-induced liver injury, are considered. Future prospects for identification of additional genetic risk factors for the various adverse drug reactions are discussed.
    Preview · Article · Jan 2013 · Genome Medicine

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