title: Genetic association study of Dickkopf-1 and sclerostin genes with paget disease of bone.
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.
authors.affiliation: CHU de Québec Research Centre, Quebec, QC, Canada.
authors.forename: Mariejka
authors.initials: M
authors.lastname: Beauregard
authors.forename: Edith
authors.initials: E
authors.lastname: Gagnon
authors.forename: Sabrina
authors.initials: S
authors.lastname: Guay-Bélanger
authors.forename: Ethel S
authors.initials: ES
authors.lastname: Siris
authors.forename: Jean
authors.initials: J
authors.lastname: Morissette
authors.forename: Jacques P
authors.initials: JP
authors.lastname: Brown
authors.forename: Laëtitia
authors.initials: L
authors.lastname: Michou
mesh_terms: D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010001:Osteitis Deformans / Q000453:epidemiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics
chemical_list: C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D022821:RNA Splice Sites; C013247:sclerotin