title: Functional polymorphisms in the P2X7 receptor gene are associated with stress fracture injury.
abstract: Military recruits and elite athletes are susceptible to stress fracture injuries. Genetic predisposition has been postulated to have a role in their development. The P2X7 receptor (P2X7R) gene, a key regulator of bone remodelling, is a genetic candidate that may contribute to stress fracture predisposition. The aim of this study is to evaluate the putative contribution of P2X7R to stress fracture injury in two separate cohorts, military personnel and elite athletes. In 210 Israeli Defense Forces (IDF) military conscripts, stress fracture injury was diagnosed (n = 43) based on symptoms and a positive bone scan. In a separate cohort of 518 elite athletes, self-reported medical imaging scan-certified stress fracture injuries were recorded (n = 125). Non-stress fracture controls were identified from these cohorts who had a normal bone scan or no history or symptoms of stress fracture injury. Study participants were genotyped for functional SNPs within the P2X7R gene using proprietary fluorescence-based competitive allele-specific PCR assay. Pearson's chi-squared (χ (2)) tests, corrected for multiple comparisons, were used to assess associations in genotype frequencies. The variant allele of P2X7R SNP rs3751143 (Glu496Ala-loss of function) was associated with stress fracture injury, whilst the variant allele of rs1718119 (Ala348Thr-gain of function) was associated with a reduced occurrence of stress fracture injury in military conscripts (P < 0.05). The association of the variant allele of rs3751143 with stress fractures was replicated in elite athletes (P < 0.05), whereas the variant allele of rs1718119 was also associated with reduced multiple stress fracture cases in elite athletes (P < 0.05). The association between independent P2X7R polymorphisms with stress fracture prevalence supports the role of a genetic predisposition in the development of stress fracture injury.
authors.affiliation: Musculoskeletal Physiology Research Group, Sport, Health and Performance Enhancement Research Centre, Nottingham Trent University, Clifton Lane, Nottingham, NG11 8NS, UK. ian.varley@ntu.ac.uk.
authors.forename: Ian
authors.initials: I
authors.lastname: Varley
authors.affiliation: Department of Occupational Medicine, Headquarters Army Recruiting and Training Division, Trenchard Lines, Upavon, Pewsey, Wilts SN9 6BE, UK. julie.greeves143@mod.uk.
authors.forename: Julie P
authors.initials: JP
authors.lastname: Greeves
authors.affiliation: Musculoskeletal Physiology Research Group, Sport, Health and Performance Enhancement Research Centre, Nottingham Trent University, Clifton Lane, Nottingham, NG11 8NS, UK. craig.sale@ntu.ac.uk.
authors.forename: Craig
authors.initials: C
authors.lastname: Sale
authors.affiliation: The Susanne Levy Gertner Oncogenetics Unit, Sheba Medical Center, Tel-Hashomer, Israel. eitan.friedman@sheba.health.gov.il.
authors.forename: Eitan
authors.initials: E
authors.lastname: Friedman
authors.affiliation: Ariel and Heller Institue, Sheba Medical Center, Ariel University, Ramat Gen, Israel. dani.moran@sheba.health.gov.il.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Moran
authors.affiliation: Ariel and Heller Institue, Sheba Medical Center, Ariel University, Ramat Gen, Israel. ran.yanovich@sheba.health.gov.il.
authors.forename: Ran
authors.initials: R
authors.lastname: Yanovich
authors.affiliation: Bone and Joint Research Group, Department of Musculoskeletal Biology, Institute of Ageing and Chronic Diseases, Faculty of Health and Life Sciences, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK. P.Wilson@liverpool.ac.uk.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Wilson
authors.affiliation: The Mellanby Centre for Bone Research, Department of Human Metabolism, The University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK. a.gartland@sheffield.ac.uk.
authors.forename: Alison
authors.initials: A
authors.lastname: Gartland
authors.affiliation: Musculoskeletal Physiology Research Group, Sport, Health and Performance Enhancement Research Centre, Nottingham Trent University, Clifton Lane, Nottingham, NG11 8NS, UK. david.hughes02@ntu.ac.uk.
authors.forename: David C
authors.initials: DC
authors.lastname: Hughes
authors.affiliation: Canadian Sport Institute Pacific, Pacific Institute for Sport Excellence, Victoria, BC, V9E 2C5, Canada. tstellingwerff@csipacific.ca.
authors.forename: Trent
authors.initials: T
authors.lastname: Stellingwerff
authors.affiliation: Cardiff School of Sport, Cardiff Metropolitan University, Cardiff, Wales, UK. cranson@cardiffmet.ac.uk.
authors.forename: Craig
authors.initials: C
authors.lastname: Ranson
authors.affiliation: Norwich Medical School, University of East Anglia, Norwich, Norfolk, NR4 7TJ, UK. W.Fraser@uea.ac.uk.|Norfolk and Norwich University Hospital, Norfolk, NR4 7UY, UK. W.Fraser@uea.ac.uk.
authors.forename: William D
authors.initials: WD
authors.lastname: Fraser
authors.affiliation: Bone and Joint Research Group, Department of Musculoskeletal Biology, Institute of Ageing and Chronic Diseases, Faculty of Health and Life Sciences, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK. J.A.Gallagher@liverpool.ac.uk.
authors.forename: James A
authors.initials: JA
authors.lastname: Gallagher
mesh_terms: D000328:Adult; D000483:Alleles; D056352:Athletes; D016723:Bone Remodeling / Q000235:genetics; D015331:Cohort Studies; D004247:DNA / Q000235:genetics; D005260:Female; D015775:Fractures, Stress / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007557:Israel; D008297:Male; D008889:Military Personnel; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D058486:Receptors, Purinergic P2X7 / Q000235:genetics*; D055815:Young Adult
chemical_list: D058486:Receptors, Purinergic P2X7; D004247:DNA
keywords: Bone; P2X7 receptor; Stress fracture injury
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