Fung, PL; (2015) The GENVABO study – genetic variants as biomarkers of jaw osteonecrosis associated with bisphosphonates: a large, multicentre genome-wide association study and detailed analyses of clinical phenotype. Doctoral thesis , UCL (University College London).

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Abstract

Osteonecrosis of the jaw (ONJ) is a potentially severe adverse effect of bisphosphonates. It can cause persistent pain and infection to the jawbones, and is currently considered incurable. ONJ occurs in a subset of individuals exposed to bisphosphonates (≤7%). Although a number of clinical risk factors, such as dentoalveolar surgery and dental infection, can increase the risk of ONJ development, there remains a number of patients who do not present with these clinical risk factors. Therefore, a genetic predisposition has been proposed. Genome-wide association studies (GWAS), widely performed in pharmacogenomics and successful in other drug side effects, have also been attempted in bisphosphonates-associated ONJ. However, possibly due to small cohort sizes (≤30 cases), these studies failed to detect any significant genetic risk factors. The aim of this thesis is to present the results of a large, multicentre GWAS, coupled with detailed analyses of clinical phenotype. 393 ONJ cases were recruited from 23 clinical centres worldwide. All cases were thoroughly phenotyped and adjudicated by specialist multidisciplinary teams. Random effects logistic regressions (Stata v12.1) were used for clinical risk factor analyses. All samples were genotyped using Illumina® Human1M Omni Express Beadchip (1,072,820 probes) and were compared with 2,554 genetically-matched population controls from publicly available sources. Genotype statistical analysis was performed in PLINK. Risk factors including advanced age, longer bisphosphonates duration, other cancers and use of steroids were found statistically significant (p<0.05). With extreme phenotyping, i.e. non-surgery triggered ONJ cases versus the population controls, for the first time, a genome-wide significant single nucleotide polymorphism was identified: rs12440268 at TJP1 gene (p=1.21E-8). Individuals positive for this marker were nearly three times more likely to develop ONJ than those negative for it (OR=2.66). TJP1 encodes protein at the tight junctions, which maintain epithelial integrity. Its polymorphism may contribute to ONJ pathogenesis through impaired mucosal healing.

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