title: Genetic variation in the TNFRSF11A gene encoding RANK is associated with susceptibility to Paget's disease of bone.
abstract: RANK (receptor activator of nuclear factor-κB), encoded by TNFRSF11A, is a key protein in osteoclastogenesis. TNFRSF11A mutations cause Paget's disease of bone (PDB)-like diseases (ie, familial expansile osteolysis, expansile skeletal hyperphosphatasia, and early-onset PDB) and an osteoclast-poor form of osteopetrosis. However, no TNFRSF11A mutations have been found in classic PDB, neither in familial nor in isolated cases. To investigate the possible relationship between TNFRSF11A polymorphisms and sporadic PDB, we conducted an association study including 32 single-nucleotide polymorphisms (SNPs) in 196 Belgian sporadic PDB patients and 212 control individuals. Thirteen SNPs and 3 multimarker tests (MMTs) turned out to have a p value of between .036 and 3.17 × 10(-4) , with the major effect coming from females. Moreover, 6 SNPs and 1 MMT withstood the Bonferroni correction (p < .002). Replication studies were performed for 2 nonsynonymous SNPs (rs35211496 and rs1805034) in a Dutch and a British cohort. Interestingly, both SNPs resulted in p values ranging from .013 to 8.38 × 10(-5) in both populations. Meta-analysis over three populations resulted in p = .002 for rs35211496 and p = 1.27 × 10(-8) for rs1805034, again mainly coming from the female subgroups. In an attempt to identify the underlying causative SNP, we performed functional studies for the coding SNPs as well as resequencing efforts of a 31-kb region harboring a risk haplotype within the Belgian females. However, neither approach resulted in significant evidence for the causality of any of the tested genetic variants. Therefore, further studies are needed to identify the real cause of the increased risk to develop PDB shown to be present within TNFRSF11A.
authors.affiliation: Department of Medical Genetics, University and University Hospital of Antwerp, Antwerp, Belgium.
authors.forename: Pui Yan Jenny
authors.initials: PY
authors.lastname: Chung
authors.forename: Greet
authors.initials: G
authors.lastname: Beyens
authors.forename: Philip L
authors.initials: PL
authors.lastname: Riches
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Van Wesenbeeck
authors.forename: Fenna
authors.initials: F
authors.lastname: de Freitas
authors.forename: Karen
authors.initials: K
authors.lastname: Jennes
authors.forename: Anna
authors.initials: A
authors.lastname: Daroszewska
authors.forename: Erik
authors.initials: E
authors.lastname: Fransen
authors.forename: Steven
authors.initials: S
authors.lastname: Boonen
authors.forename: Piet
authors.initials: P
authors.lastname: Geusens
authors.forename: Filip
authors.initials: F
authors.lastname: Vanhoenacker
authors.forename: Leon
authors.initials: L
authors.lastname: Verbruggen
authors.forename: Jan
authors.initials: J
authors.lastname: Van Offel
authors.forename: Stefan
authors.initials: S
authors.lastname: Goemaere
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Zmierczak
authors.forename: René
authors.initials: R
authors.lastname: Westhovens
authors.forename: Marcel
authors.initials: M
authors.lastname: Karperien
authors.forename: Socrates
authors.initials: S
authors.lastname: Papapoulos
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Ralston
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Devogelaer
authors.forename: Wim
authors.initials: W
authors.lastname: Van Hul
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001530:Belgium; D005091:Exons / Q000235:genetics; D005260:Female; D017930:Genes, Reporter; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005828:Genetics, Population; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D008156:Luciferases / Q000378:metabolism; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D010001:Osteitis Deformans / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011786:Quality Control; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics*; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA
chemical_list: D016328:NF-kappa B; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; D008156:Luciferases