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

• Published in: Human genetics 2010-12, Vol.128 (6), p.615-626
• Main Authors: Chung, Pui Yan Jenny, Beyens, Greet, Boonen, Steven, Papapoulos, Socrates, Geusens, Piet, Karperien, Marcel, Vanhoenacker, Filip, Verbruggen, Leon, Fransen, Erik, Van Offel, Jan, Goemaere, Stefan, Zmierczak, Hans-Georg, Westhovens, René, Devogelaer, Jean-Pierre, Van Hul, Wim
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Adult; Aged; Aged, 80 and over; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Bone diseases; Classical genetics, quantitative genetics, hybrids; Diseases of the osteoarticular system; Female; Fundamental and applied biological sciences. Psychology; Gene Function; Genes; Genetic Predisposition to Disease; Genetics of eukaryotes. Biological and molecular evolution; Genome-Wide Association Study; Genomes; Genomics; Haplotypes; Health risk assessment; Hospitals; Human; Human Genetics; Humans; Macrophage Colony-Stimulating Factor - genetics; Male; Medical sciences; Membrane Proteins - chemistry; Membrane Proteins - genetics; Metabolic Diseases; Metabolism; Middle Aged; Molecular Medicine; Mutation; Original Investigation; Osteitis Deformans - genetics; Osteoporosis; Osteoporosis. Osteomalacia. Paget disease; Pagets disease; Polymorphism, Single Nucleotide; Proteins; Receptor Activator of Nuclear Factor-kappa B - genetics; Rheumatology; Transcription Factor TFIIIA - genetics
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-010-0888-2

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.