Paget's disease of bone (PDB) is, after osteoporosis, the second most common metabolic bone disorder in the elderly Caucasian population. Mutations in the sequestosome 1 gene (SQSTM1) are responsible for the etiology of PDB in a subset of patients, but the disease pathogenesis in the remaining PDB patients is still unknown. Therefore association studies investigating the relationship between genetic polymorphisms and sporadic PDB have been performed in order to find the susceptibility polymorphisms. In this paper, we sought to determine whether polymorphisms in 3 functional candidate genes play a role in the development of sporadic PDB: TNFSF11 (receptor activator of nuclear factor κB ligand, RANKL), VCP (valosin-containing protein) and IL-6 (interleukin 6). Analyzing 9 tag SNPs and 2 multi-marker tests (MMTs) in TNFSF11, 3 tag SNPs and 1 MMT in VCP and 8 tag SNPs in IL-6 in a population of 196 Belgian patients with sporadic PDB and 212 Belgian control individuals revealed that one VCP SNP (rs565070) turned out to be associated with PDB in this Belgian study population (p=5.5×10(-3)). None of the tag SNPs or MMTs selected for TNFSF11 or IL-6 was associated with PDB. Still, replication of our findings in the VCP gene in other populations is important to confirm our results. However, when combining data of VCP with those from other susceptible gene regions from previous association studies (i.e. TNFRSF11A, CSF1, OPTN and TM7SF4), independent effect of each gene region was found and the cumulative population attributable risk is 72.7%.
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