Genetics and the Elite Athlete: Our Understanding in 2020

Abstract

Modern competitive sport has evolved so much that athletes would go to great extremes to develop themselves into champions; medicine has also evolved to the point that many genetic elements have been identified to be associated with specific athletic traits, and genetic alterations are also possible. The current review examines the published literature and looks at three important factors: genetic polymorphism influencing sporting ability, gene doping and genetic tendency to injury. The ACTN3 gene has an influence on type II muscle fibres, with the R allele being advantageous to power sports like sprinting and the XX genotype being associated with lower muscle strength and sprinting ability. The ACE gene polymorphisms are associated with cardio-respiratory efficiency and could influence endurance athletes. Many other genes are being looked at, with specific focus on those that are potentially related to enhancement of athletic ability. Recognition of these specific gene polymorphisms brings into play the concept of genetic engineering in athletes, which constitutes gene doping and is outlawed. This has the potential to develop into the next big threat in elite sports; gene doping could have dangerous and even fatal outcomes, as the knowledge of gene therapy is still in its infancy. Genetic predisposition to injury is also being identified; recent publications have increased the awareness of gene polymorphisms predisposing to injuries of ligaments and tendons due to influence on collagen structure and extracellular matrix. Ongoing work is looking at identifying the same genes from different races and different sexes to see if there are quantitative racial or sexual differences. All of the above have led to serious ethical concerns; in the twenty-first century some sports associations and some countries are looking at genetic testing for their players. Unfortunately, the science is still developing, and the experience of its application is limited worldwide. Nevertheless, this field has caught the imagination of both the public and the sportsperson, and hence the concerned doctors should be aware of the potential problems and current issues involved in understanding genetic traits and polymorphisms, genetic testing and genetic engineering.

Introduction

“We used to think that our fate was in our stars, but now we know that, in large measure, our fate is in our genes”—James Watson (co-discoverer of DNA structure).

Athletic performance is generally believed to be a complex multifactorial trait influenced by both genetic and environmental factors. In the past 2 decades, there has been a steady accumulation of compelling evidence relating certain genes to sport performance, particularly power, endurance and speed [1, 2]. To date, more than 200 gene polymorphisms have been identified with association to exercise-performance traits; over 20 of these polymorphisms have been correlated with elite athletic performance and the number is only poised to grow in the near future [3, 4].

An athlete is categorised as elite if he has played any sport at a national or international level [5]. As far as genetic constitution is concerned, elite athletic performance is considered a polygenic trait by nature with each gene polymorphism or mutation making a variable contribution to the unique athletic phenotype. Therefore, the theoretical probability of being an elite athlete increases proportionately with a high number of athletic-related alleles [6, 7]. For example, the famous Finnish cross-country skier, Eero Mäntyranta, who won two gold medals in the 1964 Winter Olympics, and went on to win a total of seven Olympic medals, had a mutation in the EPO gene that increased the red blood cell level oxygen-carrying capacity by 25–50% and offered him a distinct advantage over his rivals [8]. There is growing evidence that elite or Olympic-standard athletes carry a minimum set of particular ‘performance-enhancing’ genetic mutations [2, 5].

It is not feasible to summarise all the genetic research related to sports medicine in a single article. In this narrative review, we focus on reviewing research related to two genes which have been the most widely investigated genes and have been consistently associated with endurance, power and speed in elite athletes—the ACTN3 gene and the ACE gene. We also discuss the ever-increasing role of genetic screening tests in predicting injury risk in athletes and the growing interest in gene doping which is expected to make a windfall sooner or later.

Elite Power and Sprint Performance: The ACTN3 Gene

This gene encodes the structure of a sarcomeric protein found exclusively in type II muscle fibres (fast twitch myofibres), α-actinin-3. These fibres are responsible for generating forces at high velocity during explosive or powerful activities. A single nucleotide polymorphism (SNP) has been identified which leads to a premature stop codon (X) rather than an arginine (R) at position 577. The R allele is advantageous in power sports and the RR genotype has been found to be over-represented in elite power athletes [9]. On the other hand, the XX genotype is associated with lower sprinting ability and muscle strength [10] (Table 1).

Table 1.

List of studies exploring correlation of ACTN3 gene with sports performance

Year	Study authors	Population tested	Number of athletes tested (athletes/controls)
2003	Yang [9]	Australia	301/436
2005	Niemi [20]	Finnish	68/120
2007	Yang [21]	Ethiopia	76/198
		Kenya	284/158
		Nigeria	62/60
2007	Paparini [17]	Italian	42/102
2008	Papadimitriou [16]	Greek	101/181
2008	Druzhevskaya [22]	Russia	486/1197
2008	Ahmetov [6]	Russia	456/1211
2010	Doring [23]	German, Finnish and North American	305/292
2010	Muniesa [24]	Spanish	141/123
2010	Ruiz [25]	Spanish	153/100
2010	Shang [26]	China	250/450
2011	Chiu [15]	Taiwan	168/603
2011	Gineviciene [27]	Lithuania	193/250
2012	Kikuchi [28]	Japan	135/333

Of the polymorphisms associated with elite power and sprint performance, the α-actinin-3 R577X polymorphism has provided the most consistent results across different population cohorts [11, 12]. ACTN3 is the only gene that shows a genotype and performance association across multiple cohorts of elite power athletes, and this association is strongly supported by data from an ACTN3 knockout mouse model [13]. Almost every male Olympic sprinter or power athlete tested carries the 577R allele which is a variant of the ACTN3 gene, also dubbed as the “speed gene”. [14].

The first association between ACTN3 gene and elite athletic performance was demonstrated in 2003 by Yang et al. [9]. In their case–control study, they genotyped 429 elite white athletes (the definition of ‘elite’ athlete being applied to an individual only if he/she had represented Australia at an international level) from 14 various sports. Four hundred thirty-six healthy, unrelated, white individuals were included as controls. On analysis of genotype results, they noted that sprint athletes had a lower frequency of the XX (alpha-actinin-3 null) genotype (6% v/s. 18%). Also, none of the sprint Olympians was found with the XX genotype, meaning that every Olympic-level sprint athlete had at least one copy of the gene. The sprint athlete group also had a higher frequency of the RR genotype (50% v/s. 30%) and a lower frequency of the heterozygous RX genotype (45% v/s. 52%), compared to the control population [9.]

Chiu et al. [15] noted significantly higher frequencies of ACTN3 577R allele in female Taiwanese elite international sprint swimmers compared to the general population and even in comparison to national-level swimmers. In the Greek population, frequency of the RR ACTN3 genotype in power-oriented athletes (47.94%) was significantly higher compared to the general population (25.97%) [16]. Similar association between the ACTN3 alleles and athletic performance was noted in a real-time PCR study in the Italian population [17]. In the Spanish population, Santiago et al. [18] observed a definite correlation between elite soccer players and the ACTN3 R577X genotype. Macarthur and North calculated a p value of < 0.5 × 1011 of the effect of ACTN3 genotype on sprint performance in a meta-analysis of the published data [19].

Elite Endurance and Power Performance: The ACE Gene

The ACE gene encodes the angiotensin-1 converting enzyme. The ACE I/D polymorphism in intron 16 was historically the first genetic polymorphism associated with athleticism [29]. This gene differentiates the activity of the ACE which regulates the blood pressure and hence plays a vital role in cardio-respiratory efficiency [30–33]. The I allele has been associated with endurance sport performance and the D allele has been associated with strength and power-related performance (Table 2). Jones et al. [34] reported the distribution of the II, ID and DD genotypes at about 25%, 50% and 25%, respectively. Oh [35] reported a similar distribution in a cohort of elite Korean male athletes (23%, 66% and 11%, respectively, for II, ID and DD genotypes).

Table 2.

List of studies exploring correlation of ACE gene with sports performance

Year	Study authors	Population tested	Number of athletes tested (athletes/controls)
1998	Gayagay [36]	Australia	64/118
1999	Taylor [43]	Australia	107/685
1999	Myerson [38]	UK	79//1906
2000	Alvarez [44]	Spain	60/400
2000	Rankinen [45]	Canada, Finland, America, Germany	192/189
2001	Nazarov [46]	Russia	217/449
2004	Collins [47]	South Africa	447/199
2007	Amir [41]	Israel	121/247
2009	Eynon [11]	Israel	81/240
2010	Kim [48]	Korea	155/693
2010	Ruiz [7]	Spain	153/100
2012	Kikuchi [28]	Japan	135/333
2012	Massidda [49]	Italy	42/106

The I allele is a 287-bp insertion associated with lower serum and tissue ACE activity. This leads to a corresponding increase in muscle efficiency seen in endurance athletes like elite marathon runners, rowers, mountaineers and long distance swimmers [29, 36–40]. Cieszczyk et al. [37] in a case–control study noted a significantly higher expression of the I allele in male Polish rowers (p = 0.038) compared to healthy unrelated volunteers. This reinforced similar findings observed by Gayagay et al. [36] in 64 Australian male national rowers who had overexpression of ACE 1 allele (p < 0.02) and ACE II allele (p < 0.03). Myerson et al. [38] conducted a case–control study among 495 respondents identified by the British Olympic Association. Ninety-one Olympic standard runners ranging from sprint runners (100 m) to ultra-marathon runners (48 men and 43 women; 79 Caucasians) were noted to be carrying a significant excess of both I allele (p = 0.01) and II genotype (p = 0.019). In the other 404 Olympic standard athletes from other various sports, in which endurance was not a chief requirement, there was no significant difference in the distribution of the I allele compared to controls (0.50 vs. 0.49; p = 0.526) [38]. The same research team had previously also reported the association of this I allele with improved endurance in a cohort containing British army recruits and high-altitude mountaineers [29]. However, there were some conflicting reports with endurance sport performance being linked to the D allele rather than the I allele in 121 Israeli elite endurance athletes [41]. Ma et al. [2], in their meta-analyses focussed on the association of ACE and ACTN 3 and sporting performance, noted no statistically significant association between ACE I allele and endurance sport performance, but it was highly close to be so (OR 1.13; 95% CI 0.89–1.44). However, they did observe a significant association between ACE II genotype and endurance performance (OR 1.35; 95% CI 1.17–1.55).

The D (deleted) allele is associated with higher serum and tissue ACE activity and angiotensin II which is a growth factor [1, 30, 42]. Therefore, this genotype has been linked with power-related strength gain and elite power-oriented performance like weight lifting.

Gene Doping

Introduced for the first time in 2003 in the IOC/WADA list, gene doping or cell doping was included in the 2004 World Anti-Doping Agency (WADA) prohibited list as “the non-therapeutic use of genes, genetic elements and/or cells that have the capacity to enhance athletic performance” [50]. Genetic engineering which began in the 1980s with resultant in vitro production of active physiological proteins such as insulin, erythropoietin and growth factor has undergone a very rapid evolution since then. The Genome Project unravelled the genetic codes of several diseases opening up the possibility of treatment of these diseases. Gene doping is an inevitable offshoot of gene therapy which involves injecting DNA into the body for the treatment of genetic diseases by replacing missing genes or by up-regulation or down-regulation of the activity of some deficient or harmful genes, respectively [8].

Gene doping is widely considered as the next big threat faced by the sporting world. Although no case of gene doping has been proven so far, there has been one recent instance where a top German track-and-field coach has been tried in a court of law on suspicion of having provided the rEPO gene (Repoxygen) to several of his athletes [51, 52]. The threat of gene therapy looms large especially at elite-level events like the Olympics. New technology is being developed to detect gene cheating at the Tokyo 2020 Olympics but so far it has been almost impossible to identify athletes who might have resorted to gene doping [53].

Not only can gene doping enhance performance beyond the level of pharmacological doping, it may be almost impossible to detect with the existing technology at the present time. Common proteins which could be targeted by gene doping based on animal models are erythropoietin (EPO), insulin-like growth factor 1 (IGF-1), leptin, myostatin and vascular endothelial growth factor (VEGF) [50].

The hormone EPO, mainly secreted by kidneys, increases erythropoiesis in the body with resultant increase in the oxygen-carrying capacity of the blood leading to improvement in athletic endurance performance [54, 55]. The deletion/down-regulation of myostatin gene or the insertion/up-regulation of the IGF-1 gene can lead to increase in muscle size and power as demonstrated in numerous animal studies [56, 57]. Leptin is a satiety-inducing hormone which can be used to decrease hunger and increase the rate of weight loss [58]. The VEGF can be manipulated to increase blood supply to heart, lungs, muscles, etc. with concomitant increase in endurance and stamina. Interestingly, the common cold virus is used as a vector to deliver this gene; therefore, even the detection of the virus in the body cannot be used as evidence of cell doping [59].

Research in the field of gene therapy and by extension, gene doping, is still in the experimental stage. Gene doping can be dangerous with known and several unknown risk factors and could even be fatal. For example, increased EPO levels causes increased viscosity of the blood, leading to increased risk of stroke, cardiac arrest, etc. Also, simple up-regulation of the EPO gene does not address the physiological need to down-regulate the same gene when the necessity arises. Although the same concern exists with pharmacological EPO doping, the drug is eventually metabolised by the body restoring normal EPO levels unlike gene doping wherein there is no inherent check mechanism to bring the EPO levels back to the baseline [50, 60]. Similarly, removal of myostatin gene or the addition of the IGF-1 gene may lead to disproportionately strong muscles, increasing the probability of tendon ruptures and/or fractures [56]. The use of viral vectors to introduce genes into cells brings the theoretical risk of insertional mutagenesis with the resultant chances of uncontrolled cell growth due to poor regulation, overexpression of growth factors and cytokines, eventually ending in malignancies [50].

Genetic Predisposition to Injuries

Genetic testing to screen athletes for injury risk is already a reality. Various SNPs have been identified in the last 2 decades which have been linked to tendon and ligament injuries [61]. Particularly, the COL1A1 gene rs1800012 polymorphism has been associated with reduced risk of sports-related tendon or ligament injuries, especially in ACL injuries in different population cohorts. At this polymorphic position, which is normally occupied by a G nucleotide in the majority and T nucleotide in 20% of population, a G to T transition can occur leading to a TT genotype. The T genotype leads to qualitatively superior type 1 collagen fibres. Hence, the TT genotype is deemed to be protective and is associated with decreased risk of ACL tears and Achilles tendinopathy [62–64]. Other variants in both collagen and extracellular matrix protein genes have been identified which leads to decreased risk of tendon ruptures, shoulder dislocations and the severity of muscle strains [63, 65–71].

Genetic Testing

Numerous examples of genetic testing in athletes have been seen in the past decade [69]. Two English Premier League soccer teams have introduced genetic testing for their players. Uzbekistan is introducing genetic testing into its Olympic-talent identification program. The English Institute of Sport expressed interest in providing genetic testing to Britain’s Olympic athletes in 2012. In the US, all the NCAA collegiate athletes undergo blood tests for the presence of the sickle cell trait. Australian National Rugby League players use DNA testing to tailor workouts for sprinting or explosive power lifting [69, 72–74].

The field of genetic testing in athletes has unfortunately received more attention from the popular media than the research world [73]. There are no clear guidelines on genetic testing in athletes at present. As genetic testing is becoming more popular and commercially viable, it is important to establish rules and regulations to protect the rights of the athlete. This exciting field of research holds tremendous potential for injury prevention in athletes (Table 3).

Table 3.

Timeline of genetic testing in sports

Sl no.	Year	Country	Sport	Sports association	Test
1	2001	Australia	Boxing	Professional Boxing and Martial Arts Board of Victoria	Compulsory genetic screening for APOE4 [75]
2	2005	Australia	Rugby	Sea Eagles (professional Rugby team based in Manly, Sydney)	Tested 18 of 24 players for 11 exercise-related genes [76]
3	2005	USA	Basketball	Chicago Bulls	Eddie Curry asked to undergo DNA test for hypertrophic cardiomyopathy [77]
4	2009	USA	American Football	National Football League (NFL)	DNA samples analysed from NFL linesmen—current and former [78]
5	2009	USA	Baseball	Major League Baseball	DNA tested for a prospective player from the Dominican Republic [79]
6	2010	USA	Athletics	National Collegiate Athletic Association	Mandatory sickle cell trait screening introduced after lawsuit [80]
7	2011	United Kingdom	Soccer	English Premier League	Players’ DNA samples analysed at 100 genetic loci linked to performance and risk of injuries [81]
8	2011	USA	American Football	National Football League (NFL)	Sickle cell trait and G6PD screened under the 2011 NFL collective bargaining agreement [82]
9	2012	United Kingdom	Athletics	English Institute of Sport	Considers genetic testing to assess injury risk in England’s Olympic and Paralympics athletes [83]
10	2014	United Kingdom	Soccer	Barclays Premier League	Tested DNA for 45 variants in 2 teams to adapt individual training programmes and prevent injuries [84]
11	2015	Uzbekistan	Various (swimming, soccer, rowing, etc.)	National Olympic Committee	Test for 50 gene variants to identify future champion athletes at the molecular level [85]
12	2018	China	Various	Ministry of Science and Technology/Chinese Academy of Sciences	Announces complete genome sequencing to identify athletes for Olympic Winter games 2022 to be held in Beijing [86]

Ethical Concerns

The rapid developments in the field of sports genetics has thrown up some very pertinent questions with no clear answers in sight at the moment. In a sport which is already segregated by one gene—the Y chromosome—should further segregation be allowed based on the genetic profiles of the athletes? Should ‘superhuman’ athletes be placed in a different pool than the others? Or should the genetically empowered athletes receive a ‘handicap’ to level the playing field? These are intriguing questions which have stirred a lot of heated debate with no clear winners in the recent past. The research on gene doping is still in its infancy and widespread use of gene doping is unlikely in the near future. However, with time, the question as to whether gene doping should be prohibited completely or whether it should be embraced by the sporting authorities is going to be more pertinent. There is considerable debate if athletes without the gene polymorphisms or mutations should be allowed to genetically ‘enhance’ themselves to give themselves a fighting chance to compete against the athletes with a better genetic profile [14, 87, 88]. Psychological effect of gene testing on an athlete is another ethical nightmare. Whether ‘good’ or ‘bad’, the results of a genetic screening test may put needless pressure on the athlete: the ‘pressure to perform’ in an athlete with mutations and ‘demotivation’ in an athlete without the mutations who could very well give up on sports despite the possibility of being a champion even without the ‘ideal’ genetic traits.

Conclusions

It is now clearly established that gene polymorphisms rarely act alone; the “single-gene-as-a-magic-bullet” ideology is now largely discredited. To put it in simpler terms, just the presence of a ‘speed’ or ‘endurance’ gene will not make an athlete faster or stronger. It is often a set of complex multifactorial interactions between different genes and environmental factors that influence the final outcome. However, as research in gene testing and gene therapy improves, sports authorities should be proactive and put in place a framework of regulations to handle potential legal and ethical issues.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standard statement

This article does not contain any studies with human or animal subjects performed by the any of the authors.

Informed consent

For this type of study, informed consent is not required.