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

Abstract

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<0.002). In order to confirm our findings, replication studies were performed with the 2 non-synonymous SNPs (H141Y and A192V) in 1) a Dutch cohort with 78 cases (35 females and 43 males) and 95 controls (46 females and 49 males) and 2) a British cohort with 282 cases (144 females and 138 males) and 325 controls (166 females and 159 males). Statistics of the 2 populations shows significant P-values for both SNPs: H141Y with P=0.012and P=0.028 (respectively); and A192V with P=8.8×10−5 and P=0.005 (respectively). Although the association of H141Y seems to be driven only by females (the Dutch: P=0.004 and the British: P=0.047), significance of A192V is observed in males as well as in females (the Dutch: P=0.012 and P=0.002, respectively; and the British: P=0.047 and P=0.045, respectively). Finally, meta-analysis of all 3 European populations results in P=4.73×10−8 for A192V (common OR of C allele=1.575, 95%CI: 1.339–1.852) and P=0.004 for H141Y (common OR of C allele=1.374, 95%CI: 1.111–1.700). In conclusion, these results provide a very strong indication that genetic variation within TNFRSF11A influences the risk to develop sporadic PDB. Functional studies are ongoing to check whether any of the non-synonymous SNPs is the real causative SNP.