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

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 group. 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 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 to have suffered a stress fracture while 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.

Risk factors associated with lower extremity stress fractures in runners: a systematic review with meta-analysis

“…Mechanical loading is associated with increased bone mineral density,20 thus, runners with greater training volumes should, theoretically, have higher bone mineral density. Although ORs could not computed from mean data, bone density in runners with a history of stress fracture was lower than those without stress fractures, yet greater than that of non-athletes 10.…”

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

“…In vivo, lower lumbar spine BMD [28] and an increased risk of fracture have been shown [18]. The rs1718119 polymorphism results in increased receptor functioning related to monocyte activation and increases interleukin-1 alpha and beta release (32) 107 (30) 31 (33) 99 (31) from monocytes and macrophages [33]. Recent in vivo studies have shown that the rs1718119 variant may also be related to bone phenotypes, including increased BMD in middle aged (≥50 years) and osteoporotic men and women [27,28] and a reduced susceptibility to vertebral fracture in post-menopausal women and osteoporotic men and women [25,28].…”

“…Due to the low number of female subjects, the male athletes were stratified into a male only cohort and cases of multiple stress fractures (more than one discrete occurrence at any site) for the purposes of analyses. Information on the SFEA cohort has been reported previously [31]. Ethical approval was granted by the Nottingham Trent University Ethical Review Committee, and each participant provided written informed consent prior to their involvement in the study.…”

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.…”