Low bone mineral density (BMD) is established as a primary predictor of osteoporotic risk and can also have substantial implications for athlete health and injury risk in the elite sporting environment. BMD is a highly multi-factorial phenotype influenced by diet, hormonal characteristics and physical activity. The interrelationships between such factors, and a strong genetic component, suggested to be around 50–85% at various anatomical sites, determine skeletal health throughout life. Genome-wide association studies and case–control designs have revealed many loci associated with variation in BMD. However, a number of the candidate genes identified at these loci have no known associated biological function or have yet to be replicated in subsequent investigations. Furthermore, few investigations have considered gene–environment interactions—in particular, whether specific genes may be sensitive to mechanical loading from physical activity and the outcome of such an interaction for BMD and potential injury risk. Therefore, this review considers the importance of physical activity on BMD, genetic associations with BMD and how subsequent investigation requires consideration of the interaction between these determinants. Future research using well-defined independent cohorts such as elite athletes, who experience much greater mechanical stress than most, to study such phenotypes, can provide a greater understanding of these factors as well as the biological underpinnings of such a physiologically “extreme” population. Subsequently, modification of training, exercise or rehabilitation programmes based on genetic characteristics could have substantial implications in both the sporting and public health domains once the fundamental research has been conducted successfully.
The D-variant of the angiotensin-1 converting enzyme (ACE) gene is associated with higher circulating and tissue ACE activity. Some studies have suggested a similar association of genotype with muscle strength or the gain in strength in response to training. This study has assessed the relationship between circulating ACE activity, strength, and the response to training.Eighty-one untrained men were tested for quadriceps muscle strength, and 44 of these performed an 8-wk program of dynamic strength training of the quadriceps muscle group. Venous blood was obtained for assessment of circulating ACE activity before and after the training program. ACE genotype was also determined.At baseline, circulating ACE activity was significantly correlated with isometric (r = 0.25-0.29, P < 0.02) and isokinetic (r = 0.38, P < 0.0005) quadriceps muscle strength. ACE genotype also seemed to be related to pretraining muscle strength. However, circulating ACE activity showed no significant association with the 9-14% mean increases of muscle strength in response to the training intervention. ACE genotype also showed no association with the training-induced change in muscle strength. Circulating ACE activity did not change significantly after the training program.The data support a role for ACE in the regulation of human skeletal muscle strength, but do not confirm a role in altering the response to short-term training.
The benzyloxy-substituted lactone cyclooxygenase-2 inhibitor DFB [3-[(3,4-difluorobenzyl)oxy]-5,5-dimethyl-4-[4-(methylsulfonyl)phenyl]furan-2(5H)-one] is metabolized in human and rat liver microsomal incubations and hepatocytes to a fluorescent metabolite, DFH [3-hydroxy-5,5-dimethyl-4-[4-(methylsulfonyl)phenyl]furan-2(5H)-one]. This process is CYP3A-mediated in both species, as demonstrated by incubations with recombinant CYP3A enzymes and experiments with inhibitory antibodies. Measurement of DFH fluorescence can be used as a rapid readout of CYP3A activity following microsomal or cultured hepatocyte incubations. In rat and human hepatocytes treated with prototypical inducers, the formation of DFH was linear for the first 30 min, with no secondary metabolism of DFH, such as phase II glucuronidation, observed at early time points. Using a panel of four prototypical inducers (phenobarbital, dexamethasone, phenytoin, and rifampicin), the correlation between testosterone 6β-hydroxylation in cultured human hepatocytes and CYP3A enzyme level in cell lysate was confirmed. DFB debenzylation was then shown to correlate well with testosterone 6β-hydroxylation in hepatocytes treated with these four inducers. Primary cultured rat and human hepatocyte induction assays were optimized for 24- and 96-well plates, respectively. Controls were established to evaluate whether test compounds demonstrate time-dependent CYP3A inhibition to avoid false negative results. Thus, the use of DFB, a fluorogenic CYP3A-selective probe substrate, affords a fast, efficient, and robust assay for the measurement of CYP3A induction in both rat and human cultured primary hepatocytes.
Part 1 of this genetic association series highlighted several genetic variants independently associated with elite status in rugby. However, it is highly likely that the genetic influence on elite status is polygenic due to the interaction of multiple genes. Therefore, the aim of the present study was to investigate whether polygenic profiles of elite rugby athletes differed from non-athletes utilising 13 genetic polymorphisms previously associated with tendon/ligament injury. Total genotype score (TGS) was calculated and multifactor dimensionality reduction (MDR) was used to calculate SNP-SNP epistasis interactions. Based on our elite rugby data from Part 1, mean TGS was significantly higher in elite rugby athletes (52.1 ± 10.7) than non-athletes (48.7 ± 10.8). There were more elite rugby athletes (54%) within the upper TGS quartile, and fewer (46%) within the lower quartile, compared to non-athletes (31% and 69%, respectively; P = 5·10-5), and the TGS was able to distinguish between elite rugby athletes and non-athletes (area under the curve = 0.59; 95% confidence interval 0.55-0.63; P = 9·10-7). Furthermore, MDR identified a three-SNP model of COL5A1 rs12722, COL5A1 rs3196378 and MIR608 rs4919510 that was best able to predict elite athlete status, with a greater frequency of the CC-CC-CC genotype combination in elite rugby athletes (9.8%) than non-athletes (5.3%). We propose that elite rugby athletes possess "preferable" musculoskeletal soft-tissue injury-associated polygenic profiles that have helped them achieve success in the high injury risk environment of rugby. These data may, in future, have implications for the individual management of musculoskeletal soft-tissue injury.HighlightsElite rugby athletes have preferable polygenic profiles to non-athletes in terms of genetic variants previously associated with musculoskeletal soft-tissue injury.The total genotype score was able to distinguish between elite rugby athletes and non-athletes.COL5A1 rs12722, COL5A1 rs3196378 and MIR608 rs4919510 produced the best model for predicting elite athlete status.We propose that elite rugby athletes may have an inherited advantage to achieving elite status due to an increased resistance to soft-tissue injury.
Abstract This article introduces some aspects of sports genomics in a rugby union context, considers the rugby‐specific genetic data in the published literature and outlines the next research steps required if the potential applications of genetic technology in rugby union, also identified here, are to become possible. A substantial proportion of the inter‐individual variation for many traits related to rugby performance, including strength, short‐term muscle power, VO 2 max , injury susceptibility and the likelihood of being an elite athlete is inherited and can be investigated using molecular genetic techniques. In sports genomics, significant efforts have been made in recent years to develop large DNA biobanks of elite athletes for detailed exploration of the heritable bases of those traits. However, little effort has been devoted to the study of rugby athletes, and most of the little research that has focused on rugby was conducted with small cohorts of non‐elite players. With steadily growing knowledge of the molecular mechanisms underpinning complex performance traits and the aetiology of injury, investigating sports genomics in the context of rugby is now a viable proposition and a worthwhile endeavour. The RugbyGene project we describe briefly in this article is a multi‐institutional research collaboration in rugby union that will perform molecular genetic analyses of varying complexity. Genetic tests could become useful tools for rugby practitioners in the future and provide complementary and additional information to that provided by the non‐genetic tests currently used.
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