Genetic variation in the TNFRSF11A gene encoding RANK is associated with susceptibility to Paget's disease of bone.
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.
Chung
Pui Yan Jenny
PY
Department of Medical Genetics, University and University Hospital of Antwerp, Antwerp, Belgium.
Beyens
Greet
G
Riches
Philip L
PL
Van Wesenbeeck
Liesbeth
L
de Freitas
Fenna
F
Jennes
Karen
K
Daroszewska
Anna
A
Fransen
Erik
E
Boonen
Steven
S
Geusens
Piet
P
Vanhoenacker
Filip
F
Verbruggen
Leon
L
Van Offel
Jan
J
Goemaere
Stefan
S
Zmierczak
Hans-Georg
HG
Westhovens
René
R
Karperien
Marcel
M
Papapoulos
Socrates
S
Ralston
Stuart H
SH
Devogelaer
Jean-Pierre
JP
Van Hul
Wim
W
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
D016328:NF-kappa B; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; D008156:Luciferases