Final Report Summary - GENEPAD (Genetic and Epigenetic Determinants of Paget's Disease of bone)
Project Summary
Paget’s disease of bone (PDB) is a common disease characterized by focal areas of increased bone turnover leading to symptoms of bone pain, deformity, osteoarthritis, and other complications. Genetic factors play an important role in PDB and genetic alterations in a gene called SQSTM1 are found in about 10% of PDB cases. Genetic variations located in seven additional areas of the human genome were also found to confer susceptibility to PDB and explain about 13% of the familial risk suggesting that other genetic factors remain to be identified. Moreover, these variations have no known functional effect and further research is needed to identify the actual functional genetic variants leading to the disease. The aims of this project were threefold: 1) to define the functional genetic variants in the seven susceptibility loci for PDB, 2) To identify novel genetic variants for disease susceptibility using state of the art genetic technologies, and 3) To investigate the role of epigenetic factors and their interaction with genetic factors in the development of the disease.
Project achievements:
We have found that genetic markers that predispose to PDB could be used as markers of disease severity. It is possible that with further refinement, genetic profiling may be of clinical value in identifying individuals at high risk of a severe disease who might benefit from enhanced surveillance and early intervention (Albagha et al, JBMR 2013). Our work on the identification of functional disease-predisposing genetic variants resulted in the identification of several genetic alterations in a gene called RIN3 that were highly associated with the disease (Vallet et al, Hum Mol Genet, 2015). We also found another genetic variant in a gene called OPTN which was found to regulate the gene function elucidating for the first time a role for OPTN in regulating bone metabolism (Obaid et al, Cell Reports 2015). We found that genetic variations in another gene called PML were associated with the disease and elucidated for the first time a novel role for this gene in regulating bone metabolism. PML was found to regulates the cells responsible for bone resorption by a complex mechanism involving other proteins. We performed a comprehensive investigation to identify epigenetic factors regulating susceptibility to PDB and identified several differentially methylated loci that were associated with PDB risk. These epigenetic loci were found to act independently of previously identified genetic susceptibility loci.
Project impact
The project has identified many new genetic and epigenetic factors that predispose to PDB. This has increased our understanding of disease mechanisms and identified many novel molecular pathways (OPTN, RIN3 and PML) that could form targets for new therapeutic treatment not only for Paget’s disease, but also other diseases associated with abnormal bone metabolism. Furthermore, these factors could be used as markers for disease susceptibility and severity and to assess people at risk of developing PDB later in life and target those with the highest risk for early treatment. This could provide a substantial improvement to the clinical outcome of the disease since PDB is a late-onset disease and often diagnosed at a point when irreversible skeletal damage has already occurred. A clinical trial is ongoing to assess the effectiveness of genetic profiling in disease prevention. The outcome of this project has also opened up opportunities for research into how the newly identified genetic or epigenetic factors lead to abnormal bone turnover on molecular-, cellular-, or skeletal level.
Paget’s disease of bone (PDB) is a common disease characterized by focal areas of increased bone turnover leading to symptoms of bone pain, deformity, osteoarthritis, and other complications. Genetic factors play an important role in PDB and genetic alterations in a gene called SQSTM1 are found in about 10% of PDB cases. Genetic variations located in seven additional areas of the human genome were also found to confer susceptibility to PDB and explain about 13% of the familial risk suggesting that other genetic factors remain to be identified. Moreover, these variations have no known functional effect and further research is needed to identify the actual functional genetic variants leading to the disease. The aims of this project were threefold: 1) to define the functional genetic variants in the seven susceptibility loci for PDB, 2) To identify novel genetic variants for disease susceptibility using state of the art genetic technologies, and 3) To investigate the role of epigenetic factors and their interaction with genetic factors in the development of the disease.
Project achievements:
We have found that genetic markers that predispose to PDB could be used as markers of disease severity. It is possible that with further refinement, genetic profiling may be of clinical value in identifying individuals at high risk of a severe disease who might benefit from enhanced surveillance and early intervention (Albagha et al, JBMR 2013). Our work on the identification of functional disease-predisposing genetic variants resulted in the identification of several genetic alterations in a gene called RIN3 that were highly associated with the disease (Vallet et al, Hum Mol Genet, 2015). We also found another genetic variant in a gene called OPTN which was found to regulate the gene function elucidating for the first time a role for OPTN in regulating bone metabolism (Obaid et al, Cell Reports 2015). We found that genetic variations in another gene called PML were associated with the disease and elucidated for the first time a novel role for this gene in regulating bone metabolism. PML was found to regulates the cells responsible for bone resorption by a complex mechanism involving other proteins. We performed a comprehensive investigation to identify epigenetic factors regulating susceptibility to PDB and identified several differentially methylated loci that were associated with PDB risk. These epigenetic loci were found to act independently of previously identified genetic susceptibility loci.
Project impact
The project has identified many new genetic and epigenetic factors that predispose to PDB. This has increased our understanding of disease mechanisms and identified many novel molecular pathways (OPTN, RIN3 and PML) that could form targets for new therapeutic treatment not only for Paget’s disease, but also other diseases associated with abnormal bone metabolism. Furthermore, these factors could be used as markers for disease susceptibility and severity and to assess people at risk of developing PDB later in life and target those with the highest risk for early treatment. This could provide a substantial improvement to the clinical outcome of the disease since PDB is a late-onset disease and often diagnosed at a point when irreversible skeletal damage has already occurred. A clinical trial is ongoing to assess the effectiveness of genetic profiling in disease prevention. The outcome of this project has also opened up opportunities for research into how the newly identified genetic or epigenetic factors lead to abnormal bone turnover on molecular-, cellular-, or skeletal level.