Ian Varley

RANK/RANKL/OPG pathway: Genetic associations with stress fracture period prevalence in elite athletes

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.

Functional polymorphisms in the P2X7 receptor gene are associated with stress fracture injury.

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 (χ2) 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.

Increased training volume improves bone density and cortical area in adolescent football players

Habitual football participation has been shown to be osteogenic, although the specific volume of football participation required to cause bone adaptations are not well established. The aim of the present study is to investigate tibial bone adaptations in response to 12 weeks of increased training volume in elite adolescents who are already accustomed to irregular impact training. 99 male adolescent elite footballers participated (age 16±0 y; height 1.76±0.66 m; body mass 70.2±8.3 kg). Tibial scans were performed using peripheral quantitative computed tomography immediately before and 12 weeks after an increase in football training volume. Scans were obtained at 4, 14, 38 and 66% of tibial length. Trabecular density (mg/cm3), cortical density (mg/cm3), cross-sectional area, cortical area (mm2), cortical thickness (mm) and strength strain index (mm3) were assessed. Trabecular (4%) and cortical density (14, 38%), cortical cross-sectional area (14, 38%), total cross-sectional area (66%), cortical thickness (14, 38%) and strength strain index (14, 38%) increased following 12 weeks of augmented volume training (P<0.05). Increased density of trabecular and cortical compartments and cortical thickening were shown following an increased volume of training. These adaptive responses may have been enhanced by the adolescent status of the cohort, supporting the role of early exercise intervention in improving bone strength.

Effect of carbohydrate feeding on the bone metabolic response to running

Bone resorption is increased after running, with no change in bone formation. Feeding during exercise might attenuate this increase, preventing associated problems for bone. This study investigated the immediate and short-term bone metabolic responses to carbohydrate (CHO) feeding during treadmill running. Ten men completed two 7-day trials, once being fed CHO (8% glucose immediately before, every 20 min during, and immediately after exercise at a rate of 0.7 g CHO·kg body mass−1·h−1) and once being fed placebo (PBO). On day 4 of each trial, participants completed a 120-min treadmill run at 70% of maximal oxygen consumption (V̇o2 max). Blood was taken at baseline (BASE), immediately after exercise (EE), after 60 (R1) and 120 (R2) min of recovery, and on three follow-up days (FU1-FU3). Markers of bone resorption [COOH-terminal telopeptide region of collagen type 1 (β-CTX)] and formation [NH2-terminal propeptides of procollagen type 1 (P1NP)] were measured, along with osteocalcin (OC), parathyroid hormone (PTH), albumin-adjusted calcium (ACa), phosphate, glucagon-like peptide-2 (GLP-2), interleukin-6 (IL-6), insulin, cortisol, leptin, and osteoprotogerin (OPG). Area under the curve was calculated in terms of the immediate (BASE, EE, R1, and R2) and short-term (BASE, FU1, FU2, and FU3) responses to exercise. β-CTX, P1NP, and IL-6 responses to exercise were significantly lower in the immediate postexercise period with CHO feeding compared with PBO (β-CTX: P = 0.028; P1NP: P = 0.021; IL-6: P = 0.036), although there was no difference in the short-term response (β-CTX: P = 0.856; P1NP: P = 0.721; IL-6: P = 0.327). No other variable was significantly affected by CHO feeding during exercise. We conclude that CHO feeding during exercise attenuated the β-CTX and P1NP responses in the hours but not days following exercise, indicating an acute effect of CHO feeding on bone turnover.

Keeping your eye on the rail: gaze behaviour of horse riders approaching a jump.

The gaze behaviour of riders during their approach to a jump was investigated using a mobile eye tracking device (ASL Mobile Eye). The timing, frequency and duration of fixations on the jump and the percentage of time when their point of gaze (POG) was located elsewhere were assessed. Fixations were identified when the POG remained on the jump for 100 ms or longer. The jumping skill of experienced but non-elite riders (n = 10) was assessed by means of a questionnaire. Their gaze behaviour was recorded as they completed a course of three identical jumps five times. The speed and timing of the approach was calculated. Gaze behaviour throughout the overall approach and during the last five strides before take-off was assessed following frame-by-frame analyses. Differences in relation to both round and jump number were found. Significantly longer was spent fixated on the jump during round 2, both during the overall approach and during the last five strides (p<0.05). Jump 1 was fixated on significantly earlier and more frequently than jump 2 or 3 (p<0.05). Significantly more errors were made with jump 3 than with jump 1 (p = 0.01) but there was no difference in errors made between rounds. Although no significant correlations between gaze behaviour and skill scores were found, the riders who scored higher for jumping skill tended to fixate on the jump earlier (p = 0.07), when the horse was further from the jump (p = 0.09) and their first fixation on the jump was of a longer duration (p = 0.06). Trials with elite riders are now needed to further identify sport-specific visual skills and their relationship with performance. Visual training should be included in preparation for equestrian sports participation, the positive impact of which has been clearly demonstrated in other sports.

SNPs in the vicinity of P2X7R, RANK/RANKL/OPG and Wnt Signalling Pathways and their Association with Bone Phenotypes in Academy Footballers

CONTEXT Genotype plays an important role in influencing bone phenotypes, such as bone mineral density, but the role of genotype in determining responses of bone to exercise has yet to be elucidated. OBJECTIVE To determine whether 10 SNPs associated with genes in the vicinity of P2X7R, RANK/RANKL/OPG and Wnt Signalling Pathways are associated with bone phenotypes in elite academy footballers (Soccer players) and to determine whether these genotypes are associated with training induced changes in bone. Design, participants, and methods: 99 elite academy footballers volunteered to participate. Peripheral computed tomography of the tibia (4%, 14%, 38% and 66% sites) was performed immediately before and 12 weeks after an increase in football training volume. Genotypes were determined using proprietary fluorescence-based competitive allele-specific PCR assays. RESULTS No significant genotype by time interactions were shown for any of the SNPs analysed (P > .05). A main effect of genotype was shown. SOST SNP rs1877632 (trabecular density), P2X7R SNPs rs1718119 (cortical thickness and CSA), rs3751143 (SSI, CSA, cortical CSA and periosteal circumference) RANK/RANKL/OPG SNPs rs9594738 (periosteal circumference), rs1021188 (cortical thickness and CSA) and rs9594759 (cortical density) were associated with bone phenotypes (P < .05). CONCLUSIONS No association was shown between P2X7R, RANK/RANKL/OPG and Wnt Signalling SNPs and a change in bone phenotypes following 12 weeks of increased training volume in elite academy footballers. However, SNPs were associated with bone phenotypes pre training. These data highlight the complexity of the interaction between SNPs in the vicinity of the RANK/RANKL/OPG, P2X7R and Wnt metabolic regulatory pathways and bone phenotypes in elite academy footballers.

The association of novel polymorphisms with stress fracture injury in elite athletes: further insights from the SFEA cohort

OBJECTIVES To determine, in conjunction with a wider investigation, whether 11 genetic variants in the vicinity of vitamin D, collagen and Wnt signalling pathways were associated with stress fracture injury in the Stress Fracture Elite Athlete (SFEA) cohort. DESIGN Genotype-phenotype association study. METHODS Self-reported stress fracture history and demographic data were recorded in 518 elite athletes, 449 male and 69 female (mean age 24.2±5.5 years) from the SFEA cohort. Elite athletes were assigned to two groups based on history of stress fracture injury. Data were analysed for the whole cohort and sub-stratified in to male only and multiple stress fracture cases. Genotype was determined using a proprietary fluorescence-based competitive allele-specific polymerase chain reaction assay. RESULTS SOST SNP rs1877632 and VDR SNPs rs10735810 and rs731236 were associated with stress fracture (p<0.05). In the whole cohort, rs1877632 heterozygotes and homozygotes of the rare allele combined made up 59% of stress fracture sufferers in comparison to 46% in the non-stress fracture group (p=0.05). In the multiple stress fracture cohort, homozygotes of the rare allele of rs10735810 and rs731236 showed an association with stress fracture when compared to those homozygotes for the common allele combined with heterozygotes (p=0.03; p=0.01). No significant associations were shown in the other SNPs analysed (p>0.05). CONCLUSIONS These data suggest an important role for SOST SNP rs1877632 and VDR SNPs rs10735810 and rs731236 in the pathophysiology of stress fracture. This might be due to the role of the SNPs in the regulation of bone remodelling and adaptation to mechanical loading, with potential implications for the prevention and treatment of stress fracture injuries.

Association between match activity variables, measures of fatigue and neuromuscular performance capacity following elite competitive soccer matches

Abstract The aim of the study was to assess the relationships between match activity variables, subsequent fatigue and neuromuscular performance capacity in elite soccer players. Subjects (n = 10) were professional soccer players participating in the English Championships. Match activity variables and markers of fatigue status were measured before and following two matches. Creatine kinase (CK) and muscle soreness were measured at baseline, immediately following, as well as 40 and 64 h post-match. Countermovement jump performance and perceived ratings of wellness were measured at baseline, then 40 and 64 h post-match. Relationships were shown between CK and the total number of accelerations and decelerations immediately (r = 0.63; large), 40 h (r = 0.45; moderate) and 64 h post-match (r = 0.35; moderate) (p < 0.05). Relationships between CK and total sprint distance (r = 0.39; moderate) and the number of sprints (r = 0.35; moderate) 40 h post-match (p < 0.05) were observed. Furthermore, relationships were shown between the perceived rating of wellness and number of accelerations 40 (r = 0.52; large) and 64 h (r = 0.40; moderate) post-match, sprint distance 40 h post-match (r = 0.40; moderate) and the total number of sprints 40 h post-match (r = 0.51; large) (p < 0.05). The quantification of match activity variables, particularly the total number of accelerations and decelerations and the number of sprints, provides insights into the fatigue status in elite soccer players 40 and 64 h post-match.

The current use, and opinions of elite athletes and support staff in relation to genetic testing in elite sport within the UK

The purpose of the study was to investigate the current use of genetic testing in UK elite sport and assess how genetic testing might be received by those employed in elite sport. Seventy-two elite athletes and 95 support staff at UK sports clubs and governing bodies completed an online survey of 11 questions concerning their experience of genetic testing and beliefs regarding the use of genetic testing in sport. Genetic testing related to sports performance and injury susceptibility is conducted in UK elite sport, albeit by a relatively small proportion of athletes (≤17%) and support staff (≤8%). Athletes and their support staff agree that genetics are important in determining elite status (≥79%) and appear willing to engage in genetic testing for individualising training to improve sport performance and reduce injury risk. Opinion was divided on whether genetic information should be used to identify talented athletes and influence selection, eligibility or employment status. Genetic testing for sports performance and injury susceptibility occurs in UK elite sport, however it is not commonly conducted. There is a belief that genetics is an important factor in determining an athlete and there is a willingness to engage in genetic testing for sports performance and injury susceptibility.