Genomewide Pharmacogenetics of Bisphosphonate-Induced Osteonecrosis of the Jaw: The Role of RBMS3
doi:
10.1634/theoncologist.2011-0202
The Oncologist
January 2012
theoncologist.2011-0202
Abstract
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.
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