Genetic Variation in the TNFRSF11A Gene Encoding RANK Is Associated With Susceptibility to Paget's Disease of Bone

RANK (receptor activator of nuclear factor-kappa B), 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 317 x 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 838 x 10(-5) in both populations Meta-analysis over three populations resulted in p = 002 for rs35211496 and p = 1 27 x 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 (C) 2010 American Society for Bone and Mineral Research