May 19, 2010 - Research

Genetic Variants Associated with Risk of Paget’s Disease of Bone Identified

Aching joints and bones aren’t always just a normal part of aging, and for some, they are a symptom of Paget’s disease of bone (PDB), a condition that affects more than one million people over the age of 45 in the United States.

More on Paget’s Disease

Bone tissue is constantly being recycled.   As old bone is broken down, new bone grows in to replace it.

In PDB, the breakdown process is sped up, so the rate of new bone generation must also increase.   This rapidly grown bone tends to be softer and weaker than normal.   In most people this doesn’t lead to any symptoms, but for some it can cause bone or joint pain, deformities or fractures.   Tingling or weakness can occur if deformed bones impinge on nerves.

The cause of PDB isn’t known, but there is thought to be a genetic component to the disease.

Genetics of Paget’s

Between 15% and 40% of people with the disease have an affected mother, father, sibling or child, and mutations in the SQSTM1 gene have been linked to some cases.   To find the remaining genes that predispose a person to PDB, an international team led by researchers at the University of Edinburgh analyzed the DNA of close to 1,200 people with the disease and more than 1,500 controls.   Their results, published online recently in the journal Nature Genetics, identify common variations in three separate regions of the genome contribute to differences in risk of developing the disease.

The strongest genetic association for PDB was seen with in a variant near the   CSF1, which is known to play a critical role in bone cell formation and survival. Another variant associated with PDB is located in a gene region previously   linked to familial PDB. And finally, another variant was found near a gene that encodes a protein called RANK, which is important for bone cell function.   Mutations in this gene cause bone disease in both mice and humans.   It has also been associated with bone mineral density and fracture risk.

In an interview, the study’s senior author Stuart Ralston suggested that his team’s findings could lead to a screening test for PDB.

“This is important since we know that if treatment is left too late, then irreversible damage to the bones can occur. If we were able to intervene at an early stage with preventative therapy, guided by genetic profiling, this would be a major advance,” Ralston told the BBC.

Although the SNPs described in this new study appear to account for a large portion of the genetics of PDB, the authors point out that it is likely that there are other regions of the genome that also contribute to the risk of developing the disease that were not picked up in their analysis.   They suggest that based on their success, further studies are now warranted to identify the rest of the genetic factors associated with the disease.

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