Premium
Genetic variation in the TNFRSF11A gene encoding RANK is associated with susceptibility to Paget's disease of bone
Author(s) -
Chung Pui Yan Jenny,
Beyens Greet,
Riches Philip L,
Van Wesenbeeck Liesbeth,
de Freitas Fenna,
Jennes Karen,
Daroszewska Anna,
Fransen Erik,
Boonen Steven,
Geusens Piet,
Vanhoenacker Filip,
Verbruggen Leon,
Van Offel Jan,
Goemaere Stefan,
Zmierczak HansGeorg,
Westhovens René,
Karperien Marcel,
Papapoulos Socrates,
Ralston Stuart H,
Devogelaer JeanPierre,
Van Hul Wim
Publication year - 2010
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.162
Subject(s) - gene , biology , genetics , disease , genetic variation , paget's disease of bone , rank (graph theory) , variation (astronomy) , bioinformatics , medicine , mathematics , physics , combinatorics , astrophysics
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 . © 2010 American Society for Bone and Mineral Research.