A Probable Linkage Between Familial Paget's Disease and the HLA Loci*

Tilyard, Murray; Gardner, R. J. M.; Milligan, Laura; Cleary, T. A.; Stewart, Rosemary

doi:10.1111/j.1445-5994.1982.tb03830.x

Cited by 56 publications

(20 citation statements)

References 3 publications

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“…Familial PDB has an autosomal dominant mode of inheritance with high penetrance. Linkage analysis in families initially concentrated on HLA alleles and a susceptibility locus was described on chromosome 6p21 (Tilyard et al, 1982). However, further studies, including genome wide searches, have failed to confirm this region as important in PDB Laurin et al, 2001).…”

Section: Genetics Of Pdbmentioning

confidence: 97%

Osteoclast diseases

Helfrich

2003

Microscopy Res & Technique

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Osteoclasts are the only cells capable of resorbing mineralised bone, dentine and cartilage. Osteoclasts act in close concert with bone forming osteoblasts to model the skeleton during embryogenesis and to remodel it during later life. A number of inherited human conditions are known that are primarily caused by a defect in osteoclasts. Most of these are rare monogenic disorders, but others, such as the more common Paget's disease, are complex diseases, where genetic and environmental factors combine to result in the abnormal osteoclast phenotype. Where the genetic defect gives rise to ineffective osteoclasts, such as in osteopetrosis and pycnodysostosis, the result is the presence of too much bone. However, the phenotype in many osteoclast diseases is a combination of osteosclerosis with osteolytic lesions. In such conditions, the primary defect is hyperactivity of osteoclasts, compensated by a secondary increase in osteoblast activity. Rapid progress has been made in recent years in the identification of the causative genes and in the understanding of the biological role of the proteins encoded. This review discusses the known osteoclast diseases with particular emphasis on the genetic causes and the resulting osteoclast phenotype. These human diseases highlight the critical importance of specific proteins or signalling pathways in osteoclasts.

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Section: Genetics Of Pdbmentioning

confidence: 97%

Osteoclast diseases

Helfrich

2003

Microscopy Res & Technique

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“…Some studies indicate that paramyxoviruses play a role (Kurihara et al 2006;Roodman and Windle 2005;Selby et al 2006), but there is also no doubt that genetic factors are important. Genetic linkage studies in multi-case families have identified seven chromosomal loci that could carry PDB-causing genes (PDB1-7) (Cody et al 1997;Fotino et al 1977;Good et al 2002;Good et al 2004;Haslam et al 1998;Hocking et al 2000;Hocking et al 2001;Laurin et al 2001;Tilyard et al 1982). However, until today only one such gene has been identified: the sequestosome 1 (SQSTM1) gene located in the PDB3 locus (Hocking et al 2002;Laurin et al 2002).…”

Section: Introductionmentioning

confidence: 96%

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

et al. 2010

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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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“…This is related, at least in part, to the late age of onset of the condition and the difficulty in ascertaining informative multiplex pedigree for linkage analysis. Suggestive linkage with Paget's disease of bone was first obtained with the HLA locus (chromosome 6p21.3) by Fotino et al (8) and Tilyard et al (9) Fotino et al (8) indicated a log 10 of the odds ratio (LOD) score of 2.44 at a recombination fraction of 0.108. This locus is referred to as PDB1.…”

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confidence: 99%