title: RANK/RANKL/OPG pathway: genetic associations with stress fracture period prevalence in elite athletes.
abstract: BACKGROUND
  The RANK/RANKL/OPG signalling pathway is important in the regulation of bone turnover, with single nucleotide polymorphisms (SNPs) in genes within this pathway associated with bone phenotypic adaptations.
  
  
  OBJECTIVE
  To determine whether four SNPs associated with genes in the RANK/RANKL/OPG signalling pathway were associated with stress fracture injury in elite athletes.
  
  
  METHODS
  Radiologically confirmed stress fracture history was reported in 518 elite athletes, forming the Stress Fracture Elite Athlete (SFEA) cohort. Data were analysed for the whole group and were sub-stratified into male and cases of multiple stress fracture groups. Genotypes were determined using proprietary fluorescence-based competitive allele-specific PCR assays.
  
  
  RESULTS
  SNPs rs3018362 (RANK) and rs1021188 (RANKL) were associated with stress fracture injury (P<0.05). 8.1% of the stress fracture group and 2.8% of the non-stress fracture group were homozygote for the rare allele of rs1021188. Allele frequency, heterozygotes and homozygotes for the rare allele of rs3018362 were associated with stress fracture period prevalence (P<0.05). Analysis of the male only group showed 8.2% of rs1021188 rare allele homozygotes had suffered a stress fracture whilst 2.5% of the non-stress fracture group were homozygous. In cases of multiple stress fractures, homozygotes for the rare allele of rs1021188 and individuals possessing at least one copy of the rare allele of rs4355801 (OPG) were shown to be associated with stress fracture injury (P<0.05).
  
  
  CONCLUSIONS
  The data support an association between SNPs in the RANK/RANKL/OPG signalling pathway and the development of stress fracture injury. The association of rs3018362 (RANK) and rs1021188 (RANKL) with stress fracture injury susceptibility supports their role in the maintenance of bone health and offers potential targets for therapeutic interventions.
authors.affiliation: Biomedical Life and Health Sciences Research Centre, Nottingham Trent University, Clifton Lane, Nottingham NG11 8NS, UK. Electronic address: ian.varley@ntu.ac.uk.
authors.forename: Ian
authors.initials: I
authors.lastname: Varley
authors.affiliation: Biomedical Life and Health Sciences Research Centre, Nottingham Trent University, Clifton Lane, Nottingham NG11 8NS, UK. Electronic address: david.hughes02@ntu.ac.uk.
authors.forename: David C
authors.initials: DC
authors.lastname: Hughes
authors.affiliation: Department of Occupational Medicine, Headquarters Army Recruiting and Training Division, UK. Electronic address: Julie.Greeves143@mod.uk.
authors.forename: Julie P
authors.initials: JP
authors.lastname: Greeves
authors.affiliation: Canadian Sport Institute-Pacific, Victoria, British Columbia, Canada. Electronic address: tstellingwerff@csipacific.ca.
authors.forename: Trent
authors.initials: T
authors.lastname: Stellingwerff
authors.affiliation: Cardiff School of Sport, Cardiff Metropolitan University, Cardiff, Wales, UK. Electronic address: cranson@cardiffmet.ac.uk.
authors.forename: Craig
authors.initials: C
authors.lastname: Ranson
authors.affiliation: Norwich Medical School, University of East Anglia, UK. Electronic address: W.Fraser@uea.ac.uk.
authors.forename: William D
authors.initials: WD
authors.lastname: Fraser
authors.affiliation: Biomedical Life and Health Sciences Research Centre, Nottingham Trent University, Clifton Lane, Nottingham NG11 8NS, UK. Electronic address: craig.sale@ntu.ac.uk.
authors.forename: Craig
authors.initials: C
authors.lastname: Sale
mesh_terms: D056352:Athletes; D016022:Case-Control Studies; D005260:Female; D015775:Fractures, Stress / Q000453:epidemiology* / Q000235:genetics*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D016015:Logistic Models; D008297:Male; D053244:Osteoprotegerin; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015995:Prevalence; D053245:RANK Ligand / Q000235:genetics*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B
keywords: Athletes; Bone; Genetics; SNPs; Stress fracture