Identification of novel genetic markers that predict disease severity and complications in Paget's disease of bone

Paget's disease of bone (PDB) is a common skeletal disorder affecting about 2% of people over the age of 55 in the UK. Some patients develop progressive disease complicated by deafness, bone deformity, fractures and osteoarthritis. Mutations of SQSTM1 are found in about 10% of PDB patients and are significantly associated with disease severity (Rios Visconti et al.; JBMR, 2010). Recently, seven additional susceptibility loci for PDB have been identified by GWAS in patients without SQSTM1 mutations. The aim of this study was to determine if these novel loci are also associated with clinical severity in PDB.

We analysed seven SNPs (rs10494112, rs4294134, rs2458413, rs1561570, rs10498635, rs5742915, rs3018362) associated with the development of PDB in a recent GWAS in 771 PDB patients from the PRISM study (Albagha et al.; Nat Gen, 2011). For statistical analysis, the study population was divided into 3 groups depending on the number of risk alleles carried (< 14, n = 254; 14–16, n = 254 and > 16, n = 259). We compared disease severity in each of the groups, scoring by the number of affected bones and the presence of various complications.

Total disease severity score was significantly increased in the subgroup of patients who carried > 16 risk alleles compared with the other two groups (6.24 ± 0.10 vs 5.57 ± 0.16, p < 0.0001). Patients in this group also had a greater number of affected bones (1.45 ± 0.04 vs. 1.23 ± 0.07, p < 0.009); and had previously received a greater number of treatments for PDB (2.01 ± 0.04 vs. 1.74 ± 0.07 p < 0.001). Deafness due to skull involvement was also increased in this group (10% vs. 5.8%, p = 0.037). There was no difference between the groups in quality of life scores as assessed by the SF36 questionnaire. We found that the novel risk alleles interacted with SQSTM1 mutations to affect disease severity. For example, patients with SQSTM1 mutations carrying > 16 risk alleles had a 44% increase in disease severity score as compared with patients negative for SQSTM1 mutations carrying fewer than 16 alleles (7.82 ± 0.50 vs. 5.40 ± 0.11, p < 0.001).

We conclude that the novel risk alleles identified recently not only predispose to the development of PDB but also significantly influence disease severity both alone and in combination with SQSTM1 mutations. These genetic variants could be of clinical value in identifying a subgroup of patients who are at high risk of complications and this, in turn, could be used in targeting therapy more effectively.