Title: Genetic variation in the TNFRSF11A gene encoding RANK is associated with susceptibility to Paget's disease of bone
Authors: 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, Hans-Georg
Westhovens, Rene
Karperien, Marcel
Papapoulos, Socrates
Ralston, Stuart H
Devogelaer, Jean-Pierre
Van Hul, Wim #
Issue Date: Jun-2010
Publisher: Blackwell Science, Inc.
Series Title: Journal of Bone and Mineral Research vol:25 issue:12 pages:2316-2329
Abstract: RANK (receptor activator of nuclear factor-kappaB), encoded by TNFRSF11A, is a key protein in osteoclastogenesis. TNFRSF11A mutations cause Paget's disease of bone (PDB)-like diseases (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 classical 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 controls. 13 SNPs and 3 multimarker tests (MMTs) turned out to have a p-value between 0.036 and 3.17 x 10(-4), with the major effect coming from females. Moreover, 6 SNPs and 1 MMT withstood the Bonferroni correction (p < 0.002). Replication studies were performed for 2 non-synonymous SNPs (rs35211496, rs1805034) in a Dutch and a British cohort. Interestingly, both SNPs resulted in p-values ranging from 0.013 to 8.38 x 10(-5) in both populations. Meta-analysis over 3 populations resulted in p = 0.002 for rs35211496 and p = 1.27 x 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 harbouring 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. (c) 2010 American Society for Bone and Mineral Research.
ISSN: 0884-0431
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Rheumatology Section (-)
Faculty of Bioscience Engineering
Gerontology and Geriatrics
× corresponding author
# (joint) last author

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