Genetic Analysis to Predict the Development of Paget's Disease

Paget's disease of the bone (PDB) is a skeletal disorder with a strong genetic component which can be associated with various complications such as pain, bone deformity, arthritis and deafness. Recent advances in understanding the genetic determinants of PDB offer the prospect of developing a genetic profiling test which can be offered to people with a parent or sibling with PDB to determine how likely they are to develop the disease themselves.

The aim of the study is to perform genetic testing for variants associated with PDB in people aged 45 and above who have a parent or sibling (first degree relative) with the disease. The Investigators will assess how well genetic profiling performs in predicting PDB by performing an imaging technique called a radionuclide bone scan which is a very sensitive way of detecting early PDB. This scan will be performed on entry to the study and again after five years. The reason for performing two scans five years apart because PDB becomes more common with age and so this will allow the Investigators to give an accurate indication of how good the genetic profiling test is in people at different ages. In addition to genetic profiling the investigators will analyse blood samples for biochemical markers of PDB and also test saliva and stool samples for the microbiome profile since its thought that this may influence risk of the disease as well.

In the longer term the investigators hope the study will allow them to develop a blood test to stratify for risk of PDB and use bone scans only in people who the clinicians think are at highest risk of developing the disease. This will allow people with PDB to be picked up early allowing treatment to be given in a timely manner.

Paget's disease of bone (PDB) is a common skeletal disorder characterised by increased bone turnover affecting one or more bones throughout the skeleton. The natural history of PDB is incompletely understood but it is clear that patients are often asymptomatic when the disease is at an early stage but that later in life when the patient presents clinically, irreversible skeletal damage is often present leading to various complications, some of which are irreversible. The most common symptom of PDB is bone pain which can be due to increased metabolic activity or complications such as bone deformity, secondary osteoarthritis, spinal stenosis and pathological fractures. Other complications include deafness due to involvement of the temporal bone and osteosarcoma which is rare but often fatal.

Genetic factors play an important role in PDB and people who have a family history of the disease in a first- degree relative have a seven-times increased risk of developing the disease as compared with controls. Part of the genetic risk for developing PDB is explained by inheritance of mutations in the SQSTM1 gene. Cross-sectional studies indicate that carriers of SQSTM1 mutations run a high risk of developing the disease with increasing age. However only 40% of people with a family history of PDB carry SQSTM1 mutations and current evidence suggests that the risk of PDB in people who do not carry SQSTM1 mutations is mediated by inheritance of other susceptibility alleles which individually have modest effects on the risk of developing PDB but which when combined, have additive effect on disease susceptibility. Environmental factors also play a role in PDB and in keeping with this a recent study has shown that epigenetic factors contribute to the pathogenesis of PDB and may have value as diagnostic markers for the risk of developing the disease.

It would be highly advantageous to be able to offer people with a family history of PDB a predictive test to give an indication of their personal risk of PDB. This would allow the disease to be picked up at an early stage before complications have occurred and for preventative treatment to be offered. Prevention is key since there is no evidence that treatment can prevent or reverse complications in people with established disease.

The aim of the present study is to try and identify genetic, epigenetic and other biomarkers for the development of PDB in people with a family history of the disorder in order to facilitate early diagnosis and treatment.

Eligibility Criteria:
INCLUSION CRITERIA CASES

* Family history of PDB affecting first degree relative such as a parent or sibling.
* Not already diagnosed with PDB
* Participant willing and able to consent and comply with the study protocol.
* Age \> 45 at the time of enrolment.

EXCLUSION CRITERIA CASES

* Unable or unwilling to provide informed consent
* Contraindication to radionuclide bone scan
* Already diagnosed with PDB

INCLUSION CRITERIA CONTROLS

* Spouse, partner or friend of case
* Not diagnosed with PDB
* No family history of PDB
* Participant willing and able to consent and comply with the study protocol.
* Age \> 45 at the time of enrolment

EXCLUSION CRITERIA CONTROLS

• Unable or unwilling to give informed consent