Ian Varley1, David C Hughes2, Julie P Greeves3, Trent Stellingwerff4, Craig Ranson5, William D Fraser6, Craig Sale7. 1. Biomedical Life and Health Sciences Research Centre, Nottingham Trent University, Clifton Lane, Nottingham NG11 8NS, UK. Electronic address: ian.varley@ntu.ac.uk. 2. Biomedical Life and Health Sciences Research Centre, Nottingham Trent University, Clifton Lane, Nottingham NG11 8NS, UK. Electronic address: david.hughes02@ntu.ac.uk. 3. Department of Occupational Medicine, Headquarters Army Recruiting and Training Division, UK. Electronic address: Julie.Greeves143@mod.uk. 4. Canadian Sport Institute-Pacific, Victoria, British Columbia, Canada. Electronic address: tstellingwerff@csipacific.ca. 5. Cardiff School of Sport, Cardiff Metropolitan University, Cardiff, Wales, UK. Electronic address: cranson@cardiffmet.ac.uk. 6. Norwich Medical School, University of East Anglia, UK. Electronic address: W.Fraser@uea.ac.uk. 7. Biomedical Life and Health Sciences Research Centre, Nottingham Trent University, Clifton Lane, Nottingham NG11 8NS, UK. Electronic address: craig.sale@ntu.ac.uk.
Abstract
CONTEXT: 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. DESIGN, PARTICIPANTS, AND 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.
CONTEXT: 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. DESIGN, PARTICIPANTS, AND 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: Heather Lynn; Xiaoguang Sun; Nancy Casanova; Manuel Gonzales-Garay; Christian Bime; Joe G N Garcia Journal: Antioxid Redox Signal Date: 2019-06-18 Impact factor: 8.401
Authors: Ian Varley; Julie P Greeves; Craig Sale; Eitan Friedman; Daniel S Moran; Ran Yanovich; Peter J Wilson; Alison Gartland; David C Hughes; Trent Stellingwerff; Craig Ranson; William D Fraser; James A Gallagher Journal: Purinergic Signal Date: 2016-01-29 Impact factor: 3.765
Authors: Mauricio De Castro; Leslie G Biesecker; Clesson Turner; Ruth Brenner; Catherine Witkop; Maxwell Mehlman; Chris Bradburne; Robert C Green Journal: NPJ Genom Med Date: 2016-01-13 Impact factor: 8.617
Authors: A J Herbert; A G Williams; S J Lockey; R M Erskine; C Sale; P J Hennis; S H Day; G K Stebbings Journal: Eur J Appl Physiol Date: 2021-09-22 Impact factor: 3.078