The Dawning Age of Genetic Testing for Sports Injuries

The regular demands of training and competition make professional, collegiate, and recreational athletes highly susceptible to injury. The incidence rate of injuries among National Collegiate Athletic Association (NCAA) athletes is approximately 15.47 per 1000 athlete exposures.1 Recreational distance running causes high numbers of injuries, with incidence rates estimated between 30% and 75% per person per year.2,3 Similarly, up to 75% of age-group triathletes who participate in Ironman-distance races are injured at least once each training season.4,5 Treatment of sports injuries costs at least $160 billion per year in the United States, and Major League Baseball lost $1.6 billion in payroll between 2008 and 2013 because of injuries to players.6,7 Avoiding injuries and remaining healthy is key to the success of a team or an individual athlete.8 The potential to use genetic testing to reduce sports injuries is rapidly increasing. The COL1A1 gene, for example, encodes the alpha chain of type I collagen, the major protein component of all tendons and ligaments.9,10 There is a DNA single-nucleotide polymorphism (SNP), rs1800012, in the upstream region of this gene that affects its level of expression. The majority of people carry a G nucleotide at this polymorphic position, and approximately 20% carry a T nucleotide.11 The T allele leads to increased expression of type I collagen alpha polypeptides compared with the G nucleotide, which may increase the tensile strength of tendons and ligaments.12–14 About 4% of athletes carry 2 copies of the T allele.11,14 These TT athletes show significantly decreased risk for anterior cruciate ligament (ACL) rupture and Achilles tendinopathy.14–16 Besides this polymorphism in COL1A1, there are additional DNA variants associated not only with ACL rupture and Achilles tendinopathy but also with other athletic injuries (eg, shoulder dislocations and muscle strain severity).14,17–21 There are separate studies concerning genetic polymorphisms associated with athletic performance, such as muscle contractility and V[Combining Dot Above]O2max.22,23 Genetic information of this sort has recently been used to prevent injuries and maximize athletic performance (Table 1). A professional soccer team in the English Premier League, for example, tested athletes for genetic loci associated with sports performance, and the English Institute of Sport expressed interest in providing genetic testing to Britain's Olympic athletes in 2012.34,36 Uzbekistan is introducing genetic testing into its Olympic-talent identification program, Australian National Rugby League players use DNA testing to tailor workouts for sprinting or explosive powerlifting, and 2 English Premier League soccer teams have introduced genetic testing for their players.35,37,38 In the United States, the NCAA currently requires blood draws for all NCAA collegiate athletes to test for the presence of the sickle cell trait, which is genetically determined.39TABLE 1: General Timeline of Genetic Testing in SportsSeveral direct-to-consumer genomic companies offer genetic testing to a wide range of athletes (Table 2).40 Some companies offer genetic tests that indicate risk for sports injuries, such as soft-tissue injuries and concussions. Others provide information about sports performance, muscle fiber type, and V[Combining Dot Above]O2max. DNAFit (DNAFit Ltd, London, United Kingdom) provides a service to recreational athletes, elite athletes, professional sports teams, and individuals interested in weight loss.41 23andMe (23andMe, Inc, Mountain View, California) and Pathway Genomics (Pathway Genomics, San Diego, California) include information on athletic markers as part of a wider range of genetic services.42,43 This genetic information is then used in the development of injury prevention programs tailored for each individual.44 Most direct-to-consumer companies offer information on how to alter athletic training based on an individual's genetic results. For example, DNAFit provides its customers access to a network of personal trainers, and the Stanford Sports Genetics Program provides a 60-minute consultation to each participant.41,45TABLE 2-a: Genetic Testing Companies for AthletesTABLE 2-b: Genetic Testing Companies for AthletesThe DNA polymorphisms currently used in sports were identified in studies that test a small number of candidate genes using relatively small athlete populations (typically several hundred). There is a large and rich source of additional genetic information that could be used by athletes based on genome-wide association studies (GWAS) that examine health risks in the general population. Genomic-wide association studies can test over 1 million different polymorphisms and often include tens of thousands of subjects. Therefore, the statistical power of discovering significant genetic variants that contribute to complex phenotypes is very high.46 The results from these health studies in the general population can also provide key information to athletes about their risk for injury or nutritional needs. Low bone mineral density, for example, affects both older individuals (osteoporosis and skeletal fracture) and athletes (stress fracture).47–50 A large meta-analysis assessing bone mineral density integrated the results of 17 GWAS that screened approximately 1 million SNPs in a total of 32 961 elderly individuals.51 Sixty-three SNPs associated with bone mineral density at genome-wide significance were identified. The weighted contributions of each of these 63 SNPs were combined into 1 genetic score. Elderly individuals in the highest risk category have 1.56 increased odds for osteoporosis and 1.60 increased odds for fracture. Conversely, elderly individuals in the lowest category are protected against osteoporosis and fracture (0.62 and 0.46 decreased odds, respectively).51 Genetic variants related to osteoporosis in elderly women may very well have prognostic application regarding stress fractures in young athletes. First, bone mineral density is a major determinant for stress fractures, especially among endurance athletes.47–50 Second, higher rates of osteoporosis in older women and higher rates of stress fractures in young, active women tend to appear together in the same family.52–54 Thus, the genetic score developed for low bone mineral density in the elderly could also be a powerful tool for athletes, especially endurance athletes. The sports genetics program at Stanford University uses genetic variants associated with bone mineral density—as well as other pathological or predisposing states such as osteoporosis, asthma, vitamin and mineral levels, red blood cell phenotypes, caffeine metabolism, and disc degeneration—that can be used to reduce injury risk.45,55 By incorporating results from GWAS, the Stanford Sports Genetics Program has greatly expanded the set of DNA polymorphisms that can be used to reduce sports injury risk from approximately 13 previously known polymorphisms to 195 polymorphisms now currently in use.45 It is too early to measure the effect of genetic testing on reducing the incidence of injuries or inducing behavioral changes that will promote health and/or prevent injury. It is clear that there are many genetic polymorphisms that provide information about risk for sports-related injuries and performance-related conditions. Athletes, coaches, and medical practitioners can use this information to generate personalized training regimens for athletes. It is too early, however, to gauge the effectiveness of these personalized regimens at reducing injury incidence compared with standard training. Nevertheless, any additional information about performance might be useful to help reduce injuries and maximize performance among elite athletes, who are typically early adopters of many medical treatments designed to speed recovery from injury and/or reduce pain so that they can return to play as soon as possible.56–58 For recreational athletes, the benefits of genetic testing may be small when compared with the results of increased participation in standard approaches to training.59 Besides prompting athletes to include new modifications in their training or diet, genetic knowledge may also increase compliance with currently prescribed “prehabilitation” strategies.60 As genetic testing in sports gains momentum, it is important to develop best practices to protect the legal, ethical, and social rights of the athlete. The existing guidelines regarding genetic testing of athletes are currently unclear. The Genetic Information Nondiscrimination Act of 2008 places employees in a protected statutory class and prohibits employer discrimination based on genetic information and family medical history36; it is unclear whether this act protects collegiate athletes who do not qualify as employees of universities.33,36 However, collective bargaining agreements in major league sports may permit mandated genetic testing of athletes.36 Genetic testing has the potential to empower athletes with new information that might increase their competitive edge. As teams begin to adopt genetic programs, careful steps should be taken to ensure that players are not coerced into participating as part of a screening process that determines athletic eligibility or playing time. Genetic information is growing at an exceptional rate, producing new information faster than Moore Law—which predicts that overall processing power doubles every 2 years. We anticipate that the power of genetic testing to predict the likelihood of sports-related injuries sustained by athletes will grow rapidly. This new field of study is exciting; it holds great potential for injury prevention for athletes at every level.