Susceptibility to Paget's disease of bone is influenced by a common polymorphic variant of osteoprotegerin
Susceptibility to Paget's disease of bone is influenced by a common polymorphic variant of osteoprotegerin
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DOI：
10.1359/jbmr.040602
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发表时间：
2004-09-01
影响因子：
6.2
通讯作者：
Ralston, SH
中科院分区：
文献类型：
--
作者：
Daroszewska, A;Hocking, LJ;Ralston, SH
为了阐明编码骨保护素（OPG）的TNFRSF11B基因在佩吉特骨病（PDB）中的作用，我们在690名英国受试者和66种全球家族性研究中研究了TNFRSF11B基因多态性。我们发现TNFRSF11B的G1181等位基因编码OPG蛋白密码子3的赖氨酸，易患散发性和家族性PDB。骨佩吉特病（PDB）是一种以局灶性骨转换异常为特征的常见疾病。遗传因素在PDB的发病机制中很重要，研究表明编码骨保护素（OPG）的TNFRSF11B基因失活突变导致罕见的少年Paget病综合征。在这项研究中，我们试图确定TNFRSF11B基因的多态性是否与经典PDB的发病机制有关。材料和方法：我们通过对20例PDB患者和10例对照组的近端启动子、编码外显子和内含子-外显子边界的DNA测序来筛选TNFRSF11B基因的多态性。信息丰富的单核苷酸多态性（SNP），包括G1181C SNP，预测OPG信号肽密码子3的赖氨酸-天冬酰胺替代和单倍型，与312例PDB的存在有关，而对照组为378例，并与来自66个家族性PDB的140个受影响后代的PDB传播有关。结果和结论：G1181等位基因在PDB患者中显著过度代表（chi(2) = 5.7, df = 1, p = 0.017，校正α = 0.024），相当于PDB的优势比为1.55 （95% CI 1.11-2.16）。在散发性PDB病例和对照组中，TNFRSF11B单倍型的分布显著不同（chi(2) = 30.2, df = 9, p < 0.001），这是因为病例中含有G1181等位基因的单倍型过多。家族研究表明，含有G1181等位基因的最常见单倍型在140例家族性PDB患者中的传播频率高于预期（chi(2) = 7.35, df = 1, p < 0.01），而在78例不携带SQSTM1基因突变的家族性PDB患者亚组中，传播不平衡更为明显（chi(2) = 8.44, df = 1, p < 0.005）。我们得出结论，TNFRSF11B的G1181等位基因编码OPG蛋白密码子3的赖氨酸，易导致散发性PDB和非SQSTM1突变引起的家族性PDB的发生。
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 andMethods: 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.