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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

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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 × 10−4 to 3.8 × 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 × 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 × 10−4 and 8.8 × 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.

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Acknowledgments

This work was supported by grants from the Paget Foundation, the ‘Fonds voor Wetenschappelijk onderzoek’ (FWO, G.0117.06) and a network of excellence grant (EuroBoNeT) from the European Union (FP6) to W.V.H. S.B. is senior clinical investigator of the Fund for Scientific Research, Flanders, Belgium (F.W.O.-Vlaanderen) and holder of the Leuven University Chair in Gerontology and Geriatrics.

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Authors and Affiliations

  1. Department of Medical Genetics, University and University Hospital of Antwerp, 2610, Antwerp, Belgium

    Pui Yan Jenny Chung, Greet Beyens, Erik Fransen & Wim Van Hul

  2. Musculoskeletal Research Unit, Department of Experimental Medicine, Leuven University, UZ Leuven, 3000, Leuven, Belgium

    Steven Boonen

  3. Endocrinology and Metabolic Diseases, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands

    Socrates Papapoulos

  4. Biomedical Research Institute, University of Hasselt, 3590, Diepenbeek, Belgium

    Piet Geusens

  5. Internal Medicine/Rheumatology, University Hospital, 6229 HX, Maastricht, The Netherlands

    Piet Geusens

  6. Department of Tissue Regeneration, University of Twente, 7522 NB, Enschede, The Netherlands

    Marcel Karperien

  7. Department of Radiology, University Hospital of Antwerp, 2650, Edegem, Belgium

    Filip Vanhoenacker

  8. Department of Rheumatology, UZ Brussel, 1090, Brussels, Belgium

    Leon Verbruggen

  9. Department of Immunology and Rheumatology, University Hospital of Antwerp (UZA), 2650, Edegem, Belgium

    Jan Van Offel

  10. Unit for Osteoporosis and Metabolic Bone Diseases, Ghent University Hospital, 9000, Ghent, Belgium

    Stefan Goemaere & Hans-Georg Zmierczak

  11. Department of Rheumatology, UZ KULeuven, 3000, Leuven, Belgium

    René Westhovens

  12. Department of Rheumatology, Saint-Luc University Hospital, Université Catholique de Louvain, 1200, Brussels, Belgium

    Jean-Pierre Devogelaer

  13. StatUa Center for Statistics, University of Antwerp (UA), Prinsstraat 13, 2000, Antwerp, Belgium

    Erik Fransen

  14. Centre of Medical Genetics, University of Antwerp, Prins Boudewijnlaan 43b, 2nd Floor, 2650, Edegem, Belgium

    Wim Van Hul

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  1. Pui Yan Jenny Chung
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Correspondence to Wim Van Hul.

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Chung, P.Y.J., Beyens, G., Boonen, S. et al. 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. Hum Genet 128, 615–626 (2010). https://doi.org/10.1007/s00439-010-0888-2

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