Towards a screening test for bone disease

5 May 2010

Paget’s disease of the bone (PDB) is a painful chronic disorder that typically results in enlarged and deformed bones. It is caused by the excessive breakdown and formation of bone tissue, which can also lead to weakened bones and arthritis. PDB is a late onset disease and is usually diagnosed in people over 40. Although the underlying cause is yet to be identified, it is thought to have a genetic component, as 15-20% of those affected have a first degree relative who is also affected.

Mutations in the SQSTM1 gene have been identified in some patients with PDB; however, linkage analysis has failed to identify other genes that may predispose to this condition. Identification of genes that predispose to PDB would be advantageous for early detection, allowing preventative treatment to be initiated before onset of bone damage. A recent study in Nature Genetics reports on identification of three new genes that may be associated with PDB and could offer hopes of a screening test (reported by BBC news).

In their study Albagha et al. identified three new genetic loci that may predispose to PDB through a genome-wide association study [Albagha et al (2010) Nat. Genet. Epub]. In order to identify genes other than SQSTM1 associated with disease, samples from 750 cases without mutations in the SQSTM1 gene and 1002 controls were genotyped. This led to the identification of three candidate loci strongly associated with disease,  findings that were replicated in an independent set of 500 cases and 535 controls.

The candidate loci associated with disease included the CSF1, OPTN and TNFRSF11A genes. The CSF1 and TNFRSF11A gene products are candidates for PDB susceptibility as they are both involved in bone tissue formation and survival. Studies in rodents have shown that mutations in these gene lead to osteopetrosis (thickening of the bones). The function of OPTN in bone metabolism is as yet unknown, and further studies will be needed to establish a possible role in PDB. The researchers are undertaking further studies to elucidate the mechanism by which these genes influence disease and identify other genes that contribute to disease risk.

Comment: This study has used a different approach to identify possible genes that could increase risk for PDB and added to our knowledge of this condition. However, hopes for a screening test remain somewhat premature, since development would require identification of specific causal variants that are associated with disease and their validation in the general population in order to demonstrate their ability to correctly identify those who may be at increased risk of developing PDB.

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