Osteonecrosis of jaw (ONJ) is a rare but serious adverse drug side effect, mainly
associated with the use of intravenous (IV) bisphosphonates (BPs). The purpose of
this study was to identify genetic variants associated with ONJ in patients of European
ancestry treated with IV BPs using a whole-exome sequencing (WES). The WES phase 1
included 44 multiple myeloma patients (22 ONJ cases and 22 controls) and WES phase
2 included 17 ONJ patients with solid tumors. Multivariable logistic regression analysis
was performed to estimate the odds ratios (ORs) and 95% confidence intervals (CI)
adjusting for age, gender and principal components for ancestry. Meta-analysis of
WES phase 1 and 2 was performed to estimate the combined ORs. In silico analyses were
then performed to identify expression quantitative loci (eQTL) single nucleotide polymorphisms
(SNPs) that are in high linkage disequilibrium (LD) with the top SNPs. The associations
of the potentially functional SNPs were replicated and validated in an independent
case-control study of 48 patients of European ancestry treated with IV BPs (19 ONJ
cases and 29 controls). The top SNPs in the exome-wide association meta-analysis were
two SNPs on Chromosome 10: SIRT1 SNP rs7896005 and HERC4 SNP rs3758392 with identical
OR of 0.07 (0.01-0.46) (p = 3.83*10-5 ). In the in silico functional analyses, two
promoter region SNPs (rs7894483 and rs3758391) were identified to be in high LD with
the index SNPs and are eQTLs for SIRT1 gene in whole blood in the GTEx database. The
ORs were 0.30 (0.10-0.88), 0.26 (0.12-0.55), and 0.26 (0.12-0.55) for the WES top
SNP rs7896005 and two promoter SNPs rs7894483 and rs3758391, respectively, in the
replication sample. In summary, we identified the SIRT1/HERC4 locus on Chromosome
10 to be associated with IV BPs related ONJ and two promoter SNPs that might be the
potential genetic markers for this association. This article is protected by copyright.
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