Genetic variation in the TNFRSF11A (RANK) gene contributes to the risk to develop sporadic Paget's disease of bone

Rank (receptor activator of nuclear factor-\kappaB), encoded by the TNFRSF11A gene, is one of the most important proteins in osteoclastogenesis and bone remodeling. Mutations in TNFRSF11A have been reported to cause Paget's disease of bone (PDB)-like diseases (i.e. familial expansile osteolysis, expansile skeletal hyperphosphatasia and early onset PDB) and an osteoclast-poor form of osteopetrosis. Yet, the role of the TNFRSF11A gene in classical PDB has not been investigated in detail. We have conducted an association study in 196 Belgian sporadic PDB patients (83 females and 112 males) and 212 controls (86 females and 126 males). Based on HapMap, 27 tagSNPs and 5 multimarker tests (MMTs) were selected in and around TNFRSF11A. In addition, we have included 1 non-synonymous SNP (H141Y) which is not present in HapMap. Genotyping was carried out by KASPar technique (KBioscience, UK), TaqMan assay and direct sequencing. Statistical analysis indicates that 13 SNPs and 2 MMTs are significantly associated (P-values between 0.037 and 3.17×10−4), the majority of them due to an association in the female subcohort. Six SNPs and 1 MMT withstand the Bonferroni correction (P