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Genetic Association Study of Dickkopf-1 and Sclerostin Genes with Paget Disease of Bone

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Abstract

Increased expression of DKK1 gene was reported in pagetic osteoblasts and stromal cells, and increased serum levels of DKK1 and SOST proteins were reported in patients with Paget disease of bone (PDB). This study aimed at identifying rare genetic variants of the DKK1 and SOST genes and at testing for genetic association with PDB in the French-Canadian population. Exons, promoters, and exon–intron junctions of these genes were sequenced in patients with PDB and healthy controls. An association study of Tag SNPs of both genes was also performed in 239 pagetic patients and 297 healthy individuals. Three rare variants were identified in this study, all located in the DKK1 gene: one variant in the second exon leading to alteration in a highly conserved amino acid (p.R120L), one in the 5′-untranslated region (−50 C/A), and one in a splice site of intron 1 (IVS1 184 T/C), although none of these rare variants were associated with PDB. A genetic association of a Tag SNP of the DKK1 gene was found: the G allele of rs1569198 was significantly decreased in patients in comparison to controls (42 vs. 49 %, uncorrected P = 0.03, OR = 0.77, 95 % CI 0.61–0.98). In conclusion, this study identified three rare genetic variants in DKK1 in the French-Canadian population. In addition, a weak genetic association of a common variant of DKK1, rs1569198, which is located on a predicted new acceptor site for splicing of this gene, was observed in PDB, whereas no rare variant or genetic association was found in the SOST gene.

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Acknowledgments

M. B. was supported by a summer program for medicine student award from the Canadian Institute of Health Research, followed by a scholarship of the Fonds de Recherche du Québec-Santé (FRQS) for the Master. L. M. is supported by a career award from the FRQS. This study was funded by the Canadian Institute of Health Research (catalyst Grant: Bone Health), the Fondation du CHUQ, the Groupe de Recherche en Maladies Osseuses, the Canadian Foundation for Innovation, the FRQS, Laval University, and the CHU de Québec Research Centre.

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Authors and Affiliations

  1. CHU de Québec Research Centre, Quebec, QC, Canada

    Mariejka Beauregard, Edith Gagnon, Sabrina Guay-Bélanger, Jean Morissette, Jacques P. Brown & Laëtitia Michou

  2. Department of Medicine, Laval University, Quebec, QC, Canada

    Mariejka Beauregard, Sabrina Guay-Bélanger, Jacques P. Brown & Laëtitia Michou

  3. Department of Rheumatology-S763, CHU de Québec, 2705 boulevard Laurier, Quebec, QC, G1V 4G2, Canada

    Jacques P. Brown & Laëtitia Michou

  4. Columbia University Medical Center, New York, NY, USA

    Ethel S. Siris

Authors
  1. Mariejka Beauregard
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  2. Edith Gagnon
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  3. Sabrina Guay-Bélanger
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  4. Ethel S. Siris
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  5. Jean Morissette
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  6. Jacques P. Brown
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  7. Laëtitia Michou
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Corresponding author

Correspondence to Laëtitia Michou.

Additional information

J Brown has received remuneration from Amgen, Eli Lilly, Merck, and Warner Chilcott; consultant/advisory role to Amgen, Eli Lilly, and Merck; funding from Amgen, Bristol Myers Squibb, Eli Lilly, Novartis, Merck, Pfizer, Roche, Servier, sanofi-aventis, Takeda, and Warner Chilcott; and US patent 10/484 805. All other authors have stated that they have no conflict of interest.

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Beauregard, M., Gagnon, E., Guay-Bélanger, S. et al. Genetic Association Study of Dickkopf-1 and Sclerostin Genes with Paget Disease of Bone. Calcif Tissue Int 93, 405–412 (2013). https://doi.org/10.1007/s00223-013-9762-2

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  • DOI: https://doi.org/10.1007/s00223-013-9762-2

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