New research has revealed single-nucleotide polymorphisms (SNPs) that may increase the risk of bone disease in patients with multiple myeloma (MM).
One of these SNPs affects a gene encoding osteoprotegerin (OPG), a signaling protein that helps regulate the density of bones.
In patients with MM bone disease (MBD), bones are broken down faster than they can be repaired, resulting in fractures and lesions.
OPG is known to keep the numbers of osteoclasts in check, so it follows that mutations adversely affecting the gene may contribute to excessive bone breakdown.
Richard Houlston, MD, PhD, of The Institute of Cancer Research in London, UK, and his colleagues reported these findings in Leukemia.
The researchers analyzed the DNA of 3774 MM patients and used imaging techniques to detect which of these patients had MBD and which did not. The team used statistical analysis to compare sequencing data from the group of patients who developed MBD with those who did not.
The analysis revealed 9 SNPs that showed an association with MBD and reached genome-wide significance. They were all located in the same region at 8q24.12 and were in strong linkage disequilibrium (LD).
The strongest association at 8q24.12 was observed with the SNP rs4407910, which localizes 19Kb 3’ to the gene encoding TNFRSF11B, also known as OPG (odds ratio=1.38, P=4.02×10−9).
The researchers also found a “promising association” for MBD with the SNP rs74676832 at 19q13.43, which is located within a 29 kb region of LD intergenic to ZNF444 and GALP (odds ratio=1.97, P=9.33×10–7).
The team said these findings demonstrate that germline variation influences MBD, and they highlight the importance of the RANK/RANKL/OPG pathway in MBD development.
Furthermore, the work could enable scientists to develop new strategies to prevent MBD development and identify which patients might benefit from treatment with existing bone therapies such as bisphosphonates.
“It is really important to understand why some patients with myeloma are severely affected by bone disease,” Dr Houlston said. “This study tells us that at least part of the answer is in the patient’s DNA, greatly improving our understanding of the disease.”
“We want to be able to identify which patients are most at risk and which treatments are most likely to help them. This study gives us clues that can begin to help us do this. In the longer term, understanding the factors that contributed to bone breakdown could help us find new treatments for the disease.”
