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 two nonsynonymous single nucleotide polymorphisms (SNPs) (C421T, H141Y and T575C, V192A) in the 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 the 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, cotrasfection with mutated SQSTM1 and TNFRSF11A A192 produced a level of activation of NFκB signaling greater than cotrasfection with wild-type SQSTM1 and TNFRSF11A V192, confirming genetics and clinical evidences. These results provide the first evidence that genetic variation within the OPG/RANK/RANKL system influences the severity of PBD in synergistic action with SQSTM1 gene mutations.
| Original language | English |
|---|---|
| Pages (from-to) | 443-452 |
| Number of pages | 10 |
| Journal | Journal of Bone and Mineral Research |
| Volume | 27 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 2012 |
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Keywords
- GENE-GENE INTERACTION
- NFκB ACTIVITY
- SEVERITY OF PAGET'S DISEASE OF BONE
- TNFRSF11A GENE
- V192A
ASJC Scopus subject areas
- Orthopedics and Sports Medicine
- Endocrinology, Diabetes and Metabolism
Cite this
A nonsynonymous TNFRSF11A variation increases NFκB activity and the severity of Paget's disease. / Gianfrancesco, Fernando; Rendina, Domenico; Di Stefano, Marco; Mingione, Alessandra; Esposito, Teresa; Merlotti, Daniela; Gallone, Salvatore; Magliocca, Sara; Goode, Alice; Formicola, Daniela; Morello, Giovanna; Layfield, Robert; Frattini, Annalisa; De Filippo, Gianpaolo; Nuti, Ranuccio; Searle, Mark; Strazzullo, Pasquale; Isaia, Giancarlo; Mossetti, Giuseppe; Gennari, Luigi.
In: Journal of Bone and Mineral Research, Vol. 27, No. 2, 2012, p. 443-452.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A nonsynonymous TNFRSF11A variation increases NFκB activity and the severity of Paget's disease
AU - Gianfrancesco, Fernando
AU - Rendina, Domenico
AU - Di Stefano, Marco
AU - Mingione, Alessandra
AU - Esposito, Teresa
AU - Merlotti, Daniela
AU - Gallone, Salvatore
AU - Magliocca, Sara
AU - Goode, Alice
AU - Formicola, Daniela
AU - Morello, Giovanna
AU - Layfield, Robert
AU - Frattini, Annalisa
AU - De Filippo, Gianpaolo
AU - Nuti, Ranuccio
AU - Searle, Mark
AU - Strazzullo, Pasquale
AU - Isaia, Giancarlo
AU - Mossetti, Giuseppe
AU - Gennari, Luigi
PY - 2012
Y1 - 2012
N2 - 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 two nonsynonymous single nucleotide polymorphisms (SNPs) (C421T, H141Y and T575C, V192A) in the 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 the 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, cotrasfection with mutated SQSTM1 and TNFRSF11A A192 produced a level of activation of NFκB signaling greater than cotrasfection with wild-type SQSTM1 and TNFRSF11A V192, confirming genetics and clinical evidences. These results provide the first evidence that genetic variation within the OPG/RANK/RANKL system influences the severity of PBD in synergistic action with SQSTM1 gene mutations.
AB - 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 two nonsynonymous single nucleotide polymorphisms (SNPs) (C421T, H141Y and T575C, V192A) in the 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 the 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, cotrasfection with mutated SQSTM1 and TNFRSF11A A192 produced a level of activation of NFκB signaling greater than cotrasfection with wild-type SQSTM1 and TNFRSF11A V192, confirming genetics and clinical evidences. These results provide the first evidence that genetic variation within the OPG/RANK/RANKL system influences the severity of PBD in synergistic action with SQSTM1 gene mutations.
KW - GENE-GENE INTERACTION
KW - NFκB ACTIVITY
KW - SEVERITY OF PAGET'S DISEASE OF BONE
KW - TNFRSF11A GENE
KW - V192A
UR - http://www.scopus.com/inward/record.url?scp=84856190866&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84856190866&partnerID=8YFLogxK
U2 - 10.1002/jbmr.542
DO - 10.1002/jbmr.542
M3 - Article
C2 - 21987421
AN - SCOPUS:84856190866
VL - 27
SP - 443
EP - 452
JO - Journal of Bone and Mineral Research
JF - Journal of Bone and Mineral Research
SN - 0884-0431
IS - 2
ER -