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Susceptibility to Paget's disease of bone is influenced by a common polymorphic variant of osteoprotegerin

Daroszewska, Anna; Hocking, Lynne J; McGuigan, Fiona E A LU ; Langdahl, Bente; Stone, Michael D; Cundy, Tim; Nicholson, Geoff C; Fraser, William D and Ralston, Stuart H (2004) In Journal of Bone and Mineral Research 19(9). p.11-1506
Abstract

UNLABELLED: To clarify the role of the TNFRSF11B gene encoding osteoprotegerin (OPG), in Paget's disease of bone (PDB) we studied TNFRSF11B polymorphisms in an association study of 690 UK subjects and in a worldwide familial study of 66 kindreds. We found that the G1181 allele of TNFRSF11B, encoding lysine at codon 3 of the OPG protein, predisposes to both sporadic and familial PDB.

INTRODUCTION: Paget's disease of bone (PDB) is a common disorder characterized by focal abnormalities of bone turnover. Genetic factors are important in the pathogenesis of PDB, and studies have shown that inactivating mutations of the TNFRSF11B gene, encoding osteoprotegerin (OPG), cause the rare syndrome of juvenile Paget's disease. In this study, we... (More)

UNLABELLED: To clarify the role of the TNFRSF11B gene encoding osteoprotegerin (OPG), in Paget's disease of bone (PDB) we studied TNFRSF11B polymorphisms in an association study of 690 UK subjects and in a worldwide familial study of 66 kindreds. We found that the G1181 allele of TNFRSF11B, encoding lysine at codon 3 of the OPG protein, predisposes to both sporadic and familial PDB.

INTRODUCTION: Paget's disease of bone (PDB) is a common disorder characterized by focal abnormalities of bone turnover. Genetic factors are important in the pathogenesis of PDB, and studies have shown that inactivating mutations of the TNFRSF11B gene, encoding osteoprotegerin (OPG), cause the rare syndrome of juvenile Paget's disease. In this study, we sought to determine whether polymorphisms of the TNFRSF11B gene contribute to the pathogenesis of classical PDB.

MATERIALS AND METHODS: We screened for polymorphisms of the TNFRSF11B gene by DNA sequencing of the proximal promoter, coding exons, and intron-exon boundaries in 20 PDB patients and 10 controls. Informative single nucleotide polymorphisms (SNPs), including a G1181C SNP, which predicts a lysine-asparagine substitution at codon 3 of the OPG signal peptide and haplotypes, were related to the presence of PDB in 312 cases compared with 378 controls and to transmission of PDB in 140 affected offspring from 66 kindreds with familial PDB.

RESULTS AND CONCLUSIONS: The G1181 allele was significantly over-represented in PDB patients (chi(2) = 5.7, df = 1, p = 0.017, adjusted alpha = 0.024), equivalent to an odds ratio for PDB of 1.55 (95% CI: 1.11-2.16). The distribution of TNFRSF11B haplotypes significantly differed in sporadic PDB cases and controls (chi(2) = 30.2, df = 9, p < 0.001) because of over-representation of haplotypes containing the G1181 allele in cases. The family study showed that the most common haplotype containing the G1181 allele was transmitted more frequently than expected to 140 individuals with familial PDB (chi(2) = 7.35, df = 1, p < 0.01), and the transmission disequilibrium was even more pronounced in a subgroup of 78 familial PDB patients who did not carry mutations of the SQSTM1 gene (chi(2) = 8.44, df = 1, p < 0.005). We conclude that the G1181 allele of TNFRSF11B, encoding lysine at codon 3 of the OPG protein, predisposes to the development of sporadic PDB and familial PDB that is not caused by SQSTM1 mutations.

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keywords
Aged, Aged, 80 and over, Case-Control Studies, DNA Mutational Analysis, Female, Genetic Predisposition to Disease, Humans, Male, Osteitis Deformans, Osteoprotegerin, Polymorphism, Single Nucleotide, Receptors, Tumor Necrosis Factor, Journal Article, Research Support, Non-U.S. Gov't
in
Journal of Bone and Mineral Research
volume
19
issue
9
pages
6 pages
publisher
AMBMR
external identifiers
  • scopus:16644391256
ISSN
0884-0431
DOI
10.1359/JBMR.040602
language
English
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no
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2d4db806-6c11-451e-80ab-7c6f2d3062d2
date added to LUP
2018-01-02 11:10:55
date last changed
2019-03-05 04:12:37
@article{2d4db806-6c11-451e-80ab-7c6f2d3062d2,
  abstract     = {<p>UNLABELLED: To clarify the role of the TNFRSF11B gene encoding osteoprotegerin (OPG), in Paget's disease of bone (PDB) we studied TNFRSF11B polymorphisms in an association study of 690 UK subjects and in a worldwide familial study of 66 kindreds. We found that the G1181 allele of TNFRSF11B, encoding lysine at codon 3 of the OPG protein, predisposes to both sporadic and familial PDB.</p><p>INTRODUCTION: Paget's disease of bone (PDB) is a common disorder characterized by focal abnormalities of bone turnover. Genetic factors are important in the pathogenesis of PDB, and studies have shown that inactivating mutations of the TNFRSF11B gene, encoding osteoprotegerin (OPG), cause the rare syndrome of juvenile Paget's disease. In this study, we sought to determine whether polymorphisms of the TNFRSF11B gene contribute to the pathogenesis of classical PDB.</p><p>MATERIALS AND METHODS: We screened for polymorphisms of the TNFRSF11B gene by DNA sequencing of the proximal promoter, coding exons, and intron-exon boundaries in 20 PDB patients and 10 controls. Informative single nucleotide polymorphisms (SNPs), including a G1181C SNP, which predicts a lysine-asparagine substitution at codon 3 of the OPG signal peptide and haplotypes, were related to the presence of PDB in 312 cases compared with 378 controls and to transmission of PDB in 140 affected offspring from 66 kindreds with familial PDB.</p><p>RESULTS AND CONCLUSIONS: The G1181 allele was significantly over-represented in PDB patients (chi(2) = 5.7, df = 1, p = 0.017, adjusted alpha = 0.024), equivalent to an odds ratio for PDB of 1.55 (95% CI: 1.11-2.16). The distribution of TNFRSF11B haplotypes significantly differed in sporadic PDB cases and controls (chi(2) = 30.2, df = 9, p &lt; 0.001) because of over-representation of haplotypes containing the G1181 allele in cases. The family study showed that the most common haplotype containing the G1181 allele was transmitted more frequently than expected to 140 individuals with familial PDB (chi(2) = 7.35, df = 1, p &lt; 0.01), and the transmission disequilibrium was even more pronounced in a subgroup of 78 familial PDB patients who did not carry mutations of the SQSTM1 gene (chi(2) = 8.44, df = 1, p &lt; 0.005). We conclude that the G1181 allele of TNFRSF11B, encoding lysine at codon 3 of the OPG protein, predisposes to the development of sporadic PDB and familial PDB that is not caused by SQSTM1 mutations.</p>},
  author       = {Daroszewska, Anna and Hocking, Lynne J and McGuigan, Fiona E A and Langdahl, Bente and Stone, Michael D and Cundy, Tim and Nicholson, Geoff C and Fraser, William D and Ralston, Stuart H},
  issn         = {0884-0431},
  keyword      = {Aged,Aged, 80 and over,Case-Control Studies,DNA Mutational Analysis,Female,Genetic Predisposition to Disease,Humans,Male,Osteitis Deformans,Osteoprotegerin,Polymorphism, Single Nucleotide,Receptors, Tumor Necrosis Factor,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  number       = {9},
  pages        = {11--1506},
  publisher    = {AMBMR},
  series       = {Journal of Bone and Mineral Research},
  title        = {Susceptibility to Paget's disease of bone is influenced by a common polymorphic variant of osteoprotegerin},
  url          = {http://dx.doi.org/10.1359/JBMR.040602},
  volume       = {19},
  year         = {2004},
}