Bisphosphonate-related osteonecrosis of the jaw is associated with polymorphisms of the cytochrome P450 CYP2C8 in multiple myeloma: a genome-wide single nucleotide polymorphism analysis

Abstract

We have explored the potential role of genetics in the development of osteonecrosis of the jaw (ONJ) in multiple myeloma (MM) patients under bisphosphonate therapy. A genome-wide association study was performed using 500 568 single nucleotide polymorphisms (SNPs) in 2 series of homogeneously treated MM patients, one with ONJ (22 MM cases) and another without ONJ (65 matched MM controls). Four SNPs (rs1934951, rs1934980, rs1341162, and rs17110453) mapped within the cytochrome P450-2C gene (CYP2C8) showed a different distribution between cases and controls with statistically significant differences (P = 1.07 × 10−6, P = 4.231 × 10−6, P = 6.22 × 10−6, and P = 2.15 × 10−6, respectively). SNP rs1934951 was significantly associated with a higher risk of ONJ development even after Bonferroni correction (P corrected value = .02). Genotyping results displayed an overrepresentation of the T allele in cases compared with controls (48% vs 12%). Thus, individuals homozygous for the T allele had an increased likelihood of developing ONJ (odds ratio 12.75, 95% confidence interval 3.7-43.5).

Factors affecting the effective number of tests in genetic association studies: a comparative study of three PCA-based methods

“…Supplementary Table S3 shows the estimated two Beta parameters for the CYP2D6 data 28 and the chromosome 10 data. 8 Without setting a¼1, we found that the estimate â was close to 1 for each case. In addition, the estimateb was in line with the effective number obtained by the permutation tests corresponding to either a¼1 or a was free.…”

“…In each random shuffle, the individuals were randomly assigned as either cases or controls limited to the same disease rate of the first two original case-control data. 8,28 However, for HapMap data with only healthy individuals, half of the individuals were randomly assigned as cases and the other half were assigned as controls. Keeping the genotypes fixed, the minimum P-values in all SNPs obtained from the Fisher's exact test for the permuted case-control samples was recorded in each permutation.…”

“…We will use these data to demonstrate the impact of LD measurements on calculating the effective number. The second application is a genome-wide association studies about osteonecrosis of the jaw, 8 and we selected 22 144 SNPs with MAFs 45% over 135 135.6 kb on the chromosome 10. These data are used to investigate the influence of various M and strength of dependencies.…”

“…In addition to the single nucleotide polymorphisms (SNPs) Map 1 and the haplotype map (HapMap) projects, 2,3 several large-scale studies collected genome data from diseased and normal individuals using association tests. [4][5][6][7][8][9] By comparing their allele frequencies or marker genotypes such as the SNPs, researchers try to identify candidate regions for further fine mapping. [10][11][12] High-throughput genotyping makes genome-wide association studies a realistic mapping strategy, as found in the 500 k or 300 k study.…”

Bisphosphonate-associated osteonecrosis of the jaw: A key role of inflammation?

“…NBP soft tissue toxicity would thus be the trigger leading to necrosis of the mucosa and bone [13][14][15]. Genetic variations may also constitute a risk factor; it was recently shown that ONJ is associated with gene polymorphisms in multiple myeloma patients [16,17]. Moreover, the primary disease is probably a predisposing factor as frequency of ONJ is 2 fold higher in multiple myeloma than in breast cancers despite similar NBPs treatments [6].…”