Genetic investigation of bisphosphonate-related osteonecrosis of jaw (BRONJ) via whole exome sequencing and bioinformatics

Abstract

Genetic investigation of Bisphosphonate-Related Osteonecrosis of Jaw (BRONJ) via whole exome sequencing and bioinformaticsYong Jae Ko D.D.S., M.S.D.(Directed by Prof. Dong Hoo Han, D.D.S., M.S.D., Ph.D.)Purpose: Prescription of Bisphosphonate (BP) has increased over the years along with the increase of complications associated with the use of BP. Bisphosphonate-related osteonecrosis of jaw (BRONJ) is one of the complications linked to the consumption of BP and has greatly affected patients with minor dental trauma resulting in a long healing period. Not all patients prescribed with BP experience BRONJ and it is multigenic disease possibly affected by both environmental and genetic factors reflecting distinctive phenotype. The purpose of this study is to discover genetic biomarkers associated with BRONJ via WES followed by statistical analysis and comparison with known genes. Materials & Methods: 16 individuals who have been prescribed with bisphosphonate medication were chosen and each individual’s saliva sample was collected for whole exome sequencing (WES) . Saliva sample was taken for massive sequencing and SnpEff, 1000 genomes project East Asian population, 126 healthy Korean randomized subsample originally recruited for thyroid cancer (GSK project), and Polyphen were used to filter out common variants from 16 individuals’ whole exome sequencing data. Common variants with minor allele frequencies (MAF) >= 0.05 from all randomized datasets were eliminated and different impacts (high, moderate and loss of function) were used for comparison. To examine the association between BRONJ and known genes from previous studies (VEGF, COLIAI, CYP2C8, FDPS, RBMS3, G20210A, PPARG, MMP9, RANKL, IL1B, LRP5, VDR, IGFBP7, ABCC4, MMP2, RANK, OPG, OPN, CYP19A1 and Absorption, distribution, metabolism and excretion (ADME) genes), gene lists were constructed for comparison with current study’s filtered gene lists. Results: Total of 118,856 variants were detected and 2,180 which is equivalent to 1,866 genes was recovered after the filtering step. Bioinformatics study revealed possible gene sets related to risk of developing BRONJ. Known genes associated to BRONJ from previous studies have been tested for presence in current study and only RBMS3 was detected from current study. Comparison to ADME gene lists yielded several genes in current study’s results indicating their association with BRONJ. Conclusion: Our results suggest that various genes and gene sets might have improtant role in developing BRONJ in patients with BP medication history. Also, the results confirmed the association between BRONJ and previously discovered genes such as RBMS3, ADME genes.