Department of Medical Genetics, University and University Hospital of Antwerp, Antwerp, Belgium.
J Bone Miner Res. 2010 Dec;25(12):2592-605. doi: 10.1002/jbmr.162. Epub 2010 Jun 18.
RANK (receptor activator of nuclear factor-κB), encoded by TNFRSF11A, is a key protein in osteoclastogenesis. TNFRSF11A mutations cause Paget's disease of bone (PDB)-like diseases (ie, familial expansile osteolysis, expansile skeletal hyperphosphatasia, and early-onset PDB) and an osteoclast-poor form of osteopetrosis. However, no TNFRSF11A mutations have been found in classic PDB, neither in familial nor in isolated cases. To investigate the possible relationship between TNFRSF11A polymorphisms and sporadic PDB, we conducted an association study including 32 single-nucleotide polymorphisms (SNPs) in 196 Belgian sporadic PDB patients and 212 control individuals. Thirteen SNPs and 3 multimarker tests (MMTs) turned out to have a p value of between .036 and 3.17 × 10(-4) , with the major effect coming from females. Moreover, 6 SNPs and 1 MMT withstood the Bonferroni correction (p < .002). Replication studies were performed for 2 nonsynonymous SNPs (rs35211496 and rs1805034) in a Dutch and a British cohort. Interestingly, both SNPs resulted in p values ranging from .013 to 8.38 × 10(-5) in both populations. Meta-analysis over three populations resulted in p = .002 for rs35211496 and p = 1.27 × 10(-8) for rs1805034, again mainly coming from the female subgroups. In an attempt to identify the underlying causative SNP, we performed functional studies for the coding SNPs as well as resequencing efforts of a 31-kb region harboring a risk haplotype within the Belgian females. However, neither approach resulted in significant evidence for the causality of any of the tested genetic variants. Therefore, further studies are needed to identify the real cause of the increased risk to develop PDB shown to be present within TNFRSF11A.
RANK（核因子-κB 受体激活物），由 TNFRSF11A 编码，是破骨细胞生成的关键蛋白。TNFRSF11A 突变导致 Pagets 骨病（PDB）样疾病（即家族性扩张性骨溶解症、扩张性骨骼高磷酸酶血症和早发性 PDB）和一种破骨细胞减少型成骨不全症。然而，经典 PDB 中既没有发现 TNFRSF11A 突变，也没有在家族性或孤立性病例中发现。为了研究 TNFRSF11A 多态性与散发性 PDB 之间的可能关系，我们进行了一项关联研究，包括 196 名比利时散发性 PDB 患者和 212 名对照个体的 32 个单核苷酸多态性（SNP）。13 个 SNP 和 3 个多标记测试（MMT）的 p 值在.036 到 3.17×10(-4) 之间，主要影响女性。此外，有 6 个 SNP 和 1 个 MMT 经 Bonferroni 校正后仍具有统计学意义（p<.002）。对荷兰和英国队列中的 2 个非同义 SNP（rs35211496 和 rs1805034）进行了复制研究。有趣的是，在两个群体中，这两个 SNP 的 p 值均在.013 到 8.38×10(-5) 之间。三个群体的荟萃分析结果显示，rs35211496 的 p 值为.002，rs1805034 的 p 值为 1.27×10(-8)，这主要来自女性亚组。为了确定潜在的致病 SNP，我们对编码 SNP 进行了功能研究，并对比利时女性携带风险单倍型的 31-kb 区域进行了重测序。然而，这两种方法都没有为所测试的遗传变异的任何一种提供因果关系的显著证据。因此，需要进一步的研究来确定 TNFRSF11A 中存在的增加患 PDB 风险的真正原因。
