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, selfreported 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 -016-9495-6 no history or symptoms of stress fracture injury. Study participants were genotyped for functional SNPs within the P2X7R gene using proprietary fluorescence-based competitive allelespecific 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.

SNPs in the vicinity of P2X7R, RANK/RANKL/OPG and Wnt signalling pathways and their association with bone phenotypes in academy footballers

“…Increased cortical density and thickness were associated with the rare allele of rs1718119 at the 14% and 38% tibial sites. These data support previous research showing that the rare A allele is associated with stress fracture injury in elite athletes and military personnel [9]. Stress fracture injuries commonly occur in the vicinity of the 38% site of the tibia [39] and low CSA and cortical thickness are associated with stress fracture incidence [40;41].…”

“…Bone Mineral Content (BMC) [3;5], areal Bone Mineral Density (BMD) [6] and cortical cross sectional area (CSA), circumference and thickness [7], as well as bone strength [8], have all been shown to be increased in recreational football players compared to sedentary control populations. Bone adaptions have also been shown in the same cohort of adolescent elite footballers used in the present study after only 12 weeks of increased volume of football training [9]. Despite this, negative bone related responses to exercise have been shown in football players.…”

The interactions of physical activity, exercise and genetics and their associations with bone mineral density: implications for injury risk in elite athletes

“…Stress fracture susceptibility, in relation to genetics, has also been investigated in athletes for the first time recently, with findings suggesting that athletes with specific genetic variants may have an increased vulnerability to this injury (Varley et al 2015, 2016, 2017). Interestingly, three of the same SNPs ( VDR FokI rs2228570, TNFSF11 rs1021188 and the loss of function P2RX7 rs3751143) as mentioned above, alongside TNFRSF11A rs3018362, were associated with stress fracture incidence in the Stress Fracture in Elite Athlete (SFEA) cohort.…”

“…For example, higher total BMD in weight-bearing athletes than controls was observed in the FF (7.7%) and Ff (6.9%) but not ff (1.8%) genotypes of the vitamin D (1,25-dihydroxyvitamin D 3 ) receptor ( VDR ) FokI rs2228570 polymorphism, whilst lower total BMD was only observed in the FF (− 4.5%) genotype when comparing swimmers with a control group (Nakamura et al 2002b). Additionally, variants in the purinergic receptor P2X7 ( P2RX7 ), human TNF receptor superfamily member 11a ( TNFRSF11A ) and sclerostin ( SOST ) genes have been associated with stress fracture in elite athletes (Varley et al 2015, 2016, 2017). Substantial further study is needed on candidate genes associated with BMD and other phenotypes such as stress fracture, as well as greater exploration of genes that may interact with physical activity and the implications this would have for BMD and wider application in public health and elite sport.…”

Tarsal navicular stress fractures

“…As reviewed above, anatomic and biologic risk factors can both increase a patient's risk for stress fracture. There is some evidence to suggest genetic predisposition based on a work in 210 Israel Defense Force soldiers and 518 elite athletes evaluating genetic variability in the P2X7 receptor on osteoblasts and osteoclasts [55]. In the future, targeting these patients with treatment like Vitamin D supplementation could potentially reduce the incidence of stress fracture [45].…”