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. 2016 Apr;30(4):883-8.
doi: 10.1038/leu.2015.342. Epub 2015 Dec 16.

Genetic factors influencing the risk of multiple myeloma bone disease

D C Johnson  1 , N Weinhold  2   3 , J Mitchell  4 , B Chen  5 , O W Stephens  2 , A Försti  5   6 , J Nickel  3 , M Kaiser  1 , W A Gregory  7 , D Cairns  7 , G H Jackson  8 , P Hoffmann  9   10 , M M Noethen  9   11 , J Hillengass  3 , U Bertsch  3 , B Barlogie  2 , F E Davis  2 , K Hemminki  5   6 , H Goldschmidt  3   12 , R S Houlston  1   4 , G J Morgan  2
Affiliations

Genetic factors influencing the risk of multiple myeloma bone disease

D C Johnson et al. Leukemia. 2016 Apr.

Abstract

A major complication of multiple myeloma (MM) is the development of osteolytic lesions, fractures and bone pain. To identify genetic variants influencing the development of MM bone disease (MBD), we analyzed MM patients of European ancestry (totaling 3774), which had been radiologically surveyed for MBD. Each patient had been genotyped for ~6 00 000 single-nucleotide polymorphisms with genotypes for six million common variants imputed using 1000 Genomes Project and UK10K as reference. We identified a locus at 8q24.12 for MBD (rs4407910, OPG/TNFRSF11B, odds ratio=1.38, P=4.09 × 10(-9)) and a promising association at 19q13.43 (rs74676832, odds ratio=1.97, P=9.33 × 10(-7)). Our findings demonstrate that germline variation influences MBD and highlights the importance of RANK/RANKL/OPG pathway in MBD development. These findings will contribute to the development of future strategies for prevention of MBD in the early precancerous phases of MM.

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Conflict of interest statement

GHJ has received honoraria from Celgene and Janssen-Cilag for speaking at educational meetings. GJM has participated in advisory boards for, received payment for lectures and development of educational presentations from, and has received travel support from Celgene, Novartis, Merck and Johnson & Johnson. FED has participated in advisory boards and spoken at meetings for Celgene, Ortho Biotech and Novartis, and has received travel support to attend meetings from Celgene and Ortho Biotech. JH has participated in advisory boards for Novartis, and has received travel support to attend meetings from Celgene, Janssen-Cilag and Takeda. HG has participated in advisory boards for, received payment for lectures and development of educational presentations from, and has received travel support from Celgene, Jassen-Cilag, Chugai, Novartis, Bristol-Myers Squibb, Millenium, Onyx, Amgen and Takeda. The remaining authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Association plot for combined analyses. The P-values of the association between each single-nucleotide polymorphism (SNP) and MBD. The y axis shows the −log10 P-values of each SNP analyzed, and the x axis shows their respective chromosome position. The red horizontal line corresponds to P=5.0 × 10−8. All statistical tests were two-sided.
Figure 2
Figure 2
Regional plot of association and recombination rates for the 8q24.12 locus. Plots show association results of both genotyped (triangles) and imputed (circles) SNPs and recombination rates. −log10 P-values (y axes) of the SNPs are shown according to their chromosomal positions (x axes). rs4407910 shown as a large diamond. The color intensity of each symbol reflects the extent of LD with rs4407910 white (r2=0) through to dark red (r2=1.0). Genetic recombination rates, estimated using HapMap samples from Utah residents of western and northern European ancestry (CEU), are shown with a light blue line. Physical positions are based on NCBI build 37 of the human genome. Also shown are the relative positions of genes and transcripts mapping to the region of association.
Figure 3
Figure 3
Forest plot of the ORs for the association between (a) rs4407910, (b) rs74676832 and MBD. Studies were weighted according to the inverse of the variance of the log of the OR calculated. Horizontal lines: 95% CI. Box: OR point estimate; box area is proportional to the weight of the study. Diamond (and broken line): overall summary estimate, with CI given by its width. Unbroken vertical line: null value (OR=1.0).
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References

    1. Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med 2004; 351: 1860–1873. - PubMed
    1. Palumbo A, Anderson K. Multiple myeloma. N Engl J Med 2011; 364: 1046–1060. - PubMed
    1. Saad F, Lipton A, Cook R, Chen YM, Smith M, Coleman R. Pathologic fractures correlate with reduced survival in patients with malignant bone disease. Cancer 2007; 110: 1860–1867. - PubMed
    1. Giuliani N, Rizzoli V, Roodman GD. Multiple myeloma bone disease: pathophysiology of osteoblast inhibition. Blood 2006; 108: 3992–3996. - PubMed
    1. Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Blade J et al. International staging system for multiple myeloma. J Clin Oncol 2005; 23: 3412–3420. - PubMed

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