Mutations in the SQSTM1 gene were identified as a common cause of Paget's disease of bone (PDB) but experimental evidence demonstrated that SQSTM1 mutation is not sufficient to induce PDB in vivo. Here, we identified 2 non-synonymous SNPs (C421T, H141Y and T575C, V192A) in TNFRSF11A gene, associated with PDB and with the severity of phenotype in a large population of 654 unrelated patients that were previously screened for SQSTM1 gene mutations. The largest effect was found for T575C variant, yielding an odds ratio of 1.29 (p = 0.003), with the C allele as the risk allele. Moreover, an even more significant p-value (p = 0.0002) was observed in the subgroup of patients with SQSTM1 mutation, with an odds ratio of 1.71. Interestingly patients with the C allele also showed an increased prevalence of polyostotic disease (68%, 53%, and 51% in patients with CC, CT, and TT genotypes, respectively, p = 0.01) as well as an increased number of affected skeletal sites (2.9, 2.5, and 2.0 in patients with CC, CT, and TT genotypes, respectively, p = 0.008). These differences increased when analyses were restricted to cases with SQSTM1 mutation. In human cell lines, co-trasfection with mutated SQSTM1 and TNFRSF11A(A192) produced a level of activation of NFkB signaling greater than co-trasfection with wild type SQSTM1 and TNFRSF11A(V192) confirming genetics and clinical evidences. These results provide the first evidence that genetic variation within OPG/RANK/RANKL system influences the severity of PBD in synergistic action with SQSTM1 gene mutations. © 2011 American Society for Bone and Mineral Research.
A non-synonymous TNFRSF11A variation increases NFkB activity and the severity of Paget's disease / Gianfrancesco, F., Rendina, D., Di Stefano, M., Mingione, A., Esposito, T., Merlotti, D., Gallone, S., Magliocca, S., Goode, A., Formicola, D., Morello, G., Layfield, R., Frattini, A., De Filippo, G., Nuti, R., Searle, M., Strazzullo, P., Isaia, G., Mossetti, G., Gennari, L.. - In: JOURNAL OF BONE AND MINERAL RESEARCH. - ISSN 0884-0431. - STAMPA. - J Bone Miner Res. 2011 Oct 10. doi: 10.1002/jbmr.542. [Epub ahead of print]:(2011), pp. xx-xx. [10.1002/jbmr.542]
A non-synonymous TNFRSF11A variation increases NFkB activity and the severity of Paget's disease.
RENDINA, DOMENICO;STRAZZULLO, PASQUALE;MOSSETTI, GIUSEPPE;
2011
Abstract
Mutations in the SQSTM1 gene were identified as a common cause of Paget's disease of bone (PDB) but experimental evidence demonstrated that SQSTM1 mutation is not sufficient to induce PDB in vivo. Here, we identified 2 non-synonymous SNPs (C421T, H141Y and T575C, V192A) in TNFRSF11A gene, associated with PDB and with the severity of phenotype in a large population of 654 unrelated patients that were previously screened for SQSTM1 gene mutations. The largest effect was found for T575C variant, yielding an odds ratio of 1.29 (p = 0.003), with the C allele as the risk allele. Moreover, an even more significant p-value (p = 0.0002) was observed in the subgroup of patients with SQSTM1 mutation, with an odds ratio of 1.71. Interestingly patients with the C allele also showed an increased prevalence of polyostotic disease (68%, 53%, and 51% in patients with CC, CT, and TT genotypes, respectively, p = 0.01) as well as an increased number of affected skeletal sites (2.9, 2.5, and 2.0 in patients with CC, CT, and TT genotypes, respectively, p = 0.008). These differences increased when analyses were restricted to cases with SQSTM1 mutation. In human cell lines, co-trasfection with mutated SQSTM1 and TNFRSF11A(A192) produced a level of activation of NFkB signaling greater than co-trasfection with wild type SQSTM1 and TNFRSF11A(V192) confirming genetics and clinical evidences. These results provide the first evidence that genetic variation within OPG/RANK/RANKL system influences the severity of PBD in synergistic action with SQSTM1 gene mutations. © 2011 American Society for Bone and Mineral Research.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
