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Please use this identifier to cite or link to this item: http://hdl.handle.net/1942/11487

Title: The majority of the genetic risk for Paget's disease of bone is explained by genetic variants close to the CSF1, OPTN, TM7SF4, and TNFRSF11A genes
Authors: Chung, Pui Yan Jenny
Beyens, Greet
Boonen, Steven
Papapoulos, Socrates
Karperien, Marcel
Vanhoenacker, Filip
Verbruggen, Leon
Fransen, Erik
Van Offel, Jan
Goemaere, Stefan
Zmierczak, Hans-Georg
Westhovens, Rene
Devogelaer, Jean-Pierre
Van Hul, Wim
Issue Date: 2010
Publisher: SPRINGER
Citation: HUMAN GENETICS, 128 (6). p. 615-626
Abstract: Paget's disease of bone (PDB) is one of the most frequent metabolic bone disorders (1-5%), next to osteoporosis, affecting individuals above age 55. Sequestosome1 mutations explain a part of the PDB patients, but still the disease pathogenesis in the remaining PDB patients is largely unknown. Therefore, association studies investigating the relationship between genetic polymorphisms and sporadic PDB have been performed to find the genetic risk variants. Previously such studies indicated a role of the OPG and RANK gene. The latter was recently confirmed in a genome-wide association study (GWAS) which also indicated the involvement of chromosomal regions harbouring the CSF1 and OPTN gene. In this study, we sought to replicate these findings in a Belgian and a Dutch population. Similar significant results were obtained for the single nucleotide polymorphisms and the haplotypes. The most significant results are found in the CSF1 gene region, followed by the OPTN and TNFRSF11A gene region (p values ranging from 1.3 x 10(-4) to 3.8 x 10(-8), OR = 1.523-1.858). We next obtained significant association with a polymorphism from the chromosomal region around the TM7SF4 gene (p = 2.7 x 10(-3), OR = 1.427), encoding DC-STAMP which did not reach genome-wide significance in the GWAS, but based on its function in osteoclasts it can be considered a strong candidate gene. After meta-analysis with the GWAS data, p values ranged between 2.6 x 10(-4) and 8.8 x 10(-32). The calculated cumulative population attributable risk of these four loci turned out to be about 67% in our two populations, indicating that most of the genetic risk for PDB is coming from genetic variants close to these four genes.
Notes: [Chung, Pui Yan Jenny; Beyens, Greet; Fransen, Erik; Van Hul, Wim] Univ & Univ Hosp Antwerp, Dept Med Genet, B-2610 Antwerp, Belgium. [Boonen, Steven] Leuven Univ, UZ Leuven, Dept Expt Med, Musculoskeletal Res Unit, B-3000 Leuven, Belgium. [Papapoulos, Socrates] Leiden Univ, Med Ctr, NL-2333 ZA Leiden, Netherlands. [Geusens, Piet] Univ Hasselt, Biomed Res Inst, B-3590 Diepenbeek, Belgium. [Geusens, Piet] Univ Hosp, NL-6229 HX Maastricht, Netherlands. [Karperien, Marcel] Univ Twente, Dept Tissue Regenerat, NL-7522 NB Enschede, Netherlands. [Vanhoenacker, Filip] Univ Antwerp Hosp, Dept Radiol, B-2650 Edegem, Belgium. [Verbruggen, Leon] UZ Brussel, Dept Rheumatol, B-1090 Brussels, Belgium. [Van Offel, Jan] Univ Hosp Antwerp UZA, Dept Immunol & Rheumatol, B-2650 Edegem, Belgium. [Goemaere, Stefan; Zmierczak, Hans-Georg] Ghent Univ Hosp, Unit Osteoporosis & Metab Bone Dis, B-9000 Ghent, Belgium. [Westhovens, Rene] UZ KULeuven, Dept Rheumatol, B-3000 Leuven, Belgium. [Devogelaer, Jean-Pierre] Catholic Univ Louvain, St Luc Univ Hosp, Dept Rheumatol, B-1200 Brussels, Belgium. [Fransen, Erik] Univ Antwerp UA, StatUa Ctr Stat, B-2000 Antwerp, Belgium. [Van Hul, Wim] Univ Antwerp, Ctr Med Genet, B-2650 Edegem, Belgium. wim.vanhul@ua.ac.be
URI: http://hdl.handle.net/1942/11487
DOI: 10.1007/s00439-010-0888-2
ISI #: 000284162200006
ISSN: 0340-6717
Category: A1
Type: Journal Contribution
Validation: ecoom, 2011
Appears in Collections: Research publications

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