Genetics of sport – Ian Craig

Is it a fad, or is it a useful tool in sports training and nutrition? Ian Craig takes a closer look at an industry rapidly gathering steam.

Genetics is becoming hard to ignore these days. Discoveries in genetics are regularly in scientific news headlines, genetic testing is increasingly being used by integrative medicine practitioners within the arena of health, and we are now very much aware that at least 50 per cent of our weight management dynamics are influenced by genetic predispositions (see FSN Mar/Apr 2012). But what about exercise and sporting performance?

It’s very obvious when we think about it: when it comes to genetics, we are extremely unique regarding sporting attributes. Most of us would not dream of being able to take on Usain Bolt over a 100m sprint, nor would we try and drop Haile Gebrselassie in a marathon race. Even when compared to other elite athletes, these two genetically endowed men are particularly good examples of genetic ‘outliers’ when it comes to their particular sporting disciplines.

You will be interested to know that within the world of sports and training, research in genetics is not too far behind our notions of personalisation. Since 2003, when the human genome was finally mapped to completion, research within the genetics of sporting performance has been prolific. It is now thought that a high percentage of the variance in athlete status is explained by additive genetic factors. For instance, a Russian study in 2009 (1) looked at endurance performance and many genes in 1423 athletes compared to 1132 controls. The researchers found that 66 per cent of the elite endurance athletes were carriers of eight or more of these endurance-related genes.

Genes have now been coded and studied, which can assist an athlete or their coach in choosing their endurance and power training sessions, understand how quickly they are likely to recover from training sessions and be aware of their genetic susceptibility for tendon and other soft tissue injuries. It is a contemporary notion that prescription exercise regimes can be tailored to the individual’s genotype. A Rugby League team in Manly, Australia (2) have claimed that they gained a competitive advantage over their rivals by using genetic testing to design the players’ training programmes in an individual way.

Genetics in lab testing for sports

With regards to the frequently asked question of whether genetic testing can be of benefit to an athlete, I would reply with these two words: “It depends.” It depends on which genes are being tested; it depends on how many genes are being tested, and most importantly, it depends on the skills of the person interpreting the information.

In an informational context, genes are only as good as the research that has already been done on them. Some genes, such as Angiotensin Converting Enzyme (ACE), have received a huge amount of research attention and are therefore very credible genes, whereas others, such as Thyroid Releasing Hormone Receptor (TRHR), only have quite specific and isolated research behind their genetic function. It is, therefore, in the hands of the lab’s education platforms and the practitioners themselves to make appropriate use of the information emanating from the various genes.

Additionally, and I can’t emphasise this enough, information about genetics is not a substitute for hard work by the practitioner or coach. A physical/physiological assessment still needs to be made, along with a detailed health and training history. Genetic testing without knowledge of the whole athlete is akin to a doctor treating a patient based on blood results, with no acknowledgement of signs and symptoms.

Assuming, however, the professional using the test information is already accomplished in the assessment and intervention of health and performance indices, genetic testing can be a very useful additional tool in their multi-disciplinary toolkit.

To add credit to the notion of genetic testing within fitness and sport, I refer you to the 2007 Position Stand of the British Association of Sports and Exercise Sciences (BASES – 3). The paper included the following statement in their conclusions: “Genetic testing might in future be used to identify those who are most likely to benefit from exercise programmes to improve health, so sport and exercise scientists should seek to generate sufficient evidence to determine whether a ‘personalised medicine’ or ‘exercise for all’ approach (or some combination of the two) is the most effective strategy to prevent and treat disease.”

I might add that BASES is quite a conservative organisation that generally doesn’t talk positively about any new notion unless the science is nicely stacked up to support its statements. Add to this the fact that 2007, when the position stand was written, was very early in the genetics of sport and health movement. The statement is more focused on health, which supports my thinking that genetics of fitness and sport are not isolated to the athletic elite. Other respected sports scientists are also putting their names to athleticogenomics, as it is also referred to. Of British significance is Dr Jamie Timmons of Loughborough University, who founded a genetics lab in 2012 and in South Africa, injury genetics expert Dr Malcolm Collins contributes to a commercial laboratory.

Within the research of athleticogenomics, what has generally happened is that single genes are identified, which are positively associated with either strength, power or endurance. Depending on the lab, the research threshold for inclusion of a gene will vary. More discernible labs will have higher thresholds, meaning fewer genes that make the grade. Having said that, ongoing research is rapid, so the number of ‘candidate’ genes should be regularly updated.

In a sports and exercise context, labs stick mostly to strength, power and endurance genes. However, functional practitioners may also be interested in physiological indices that don’t link to athletic performance in an obvious way, but when functional health is considered, it opens up many other points of interest. For example, genetics of circadian rhythms may suggest that one athlete would best exercise before work, whereas another should rather exert their body at the end of the day. One sports person may have poor genetic detoxification capabilities, whereby they should rather avoid sports products with a large collection of artificial additives.

Let’s take a look at a few of my favourite sports genes:  

Genetics of gene: ACE (Angiotensin Converting Enzyme)

ACE is the most studied of all the genes involved in sporting performance. An enzyme hydrolyses angiotensin I into angiotensin II, an important vasoconstrictor and blood pressure regulator. In normal individuals, plasma ACE levels can have as much as a five-fold inter-individual variation, and approximately half of this variation is thought to be due to a polymorphism in the ACE gene. The two ACE alleles are I (insertion) and D (deletion).

The ACE I allele has been associated with an increased percentage of slow twitch type I fibres, higher VO₂max, greater aerobic work efficiency, improved fatigue resistance, higher peripheral tissue oxygenation during exercise, greater aerobic power response to training and greater cardiac output in athletes (4). The D allele, on the other hand, is associated with greater muscle growth with weight training and being better at strength sports.

Many of the genes in the sports arena also have certain health associations. Individuals possessing the ACE D allele (in particular, the DD genotype) should be aware of hypertension and left ventricular hypertrophy due to exercise training. These individuals would be advised to monitor blood pressure regularly and to be mindful of high-intensity training, in particular, pressure holds.

Interestingly, it’s been demonstrated that individuals with the I allele (especially the II genotype), even though they have a lower overall risk of hypertension, may experience greater blood pressure increase with a high sodium (salt) intake (5,6). This has ramifications for athletes who consume electrolytes as part of their sporting diet, suggesting the potential need for personalised electrolyte formulas.

Genetics of gene: ACTN3 (Alpha-Actinin 3)

Alpha-actinins are a family of actin-binding proteins that maintain the cytoskeleton. The ACTN3 gene encodes alpha-actinin 3, which is only in fast-twitch muscle fibres. Alpha-actinins are found at the Z-line of the muscle, where they anchor actin filaments and help maintain the structure of the sarcomere.  The ACTN3 gene contains a polymorphism which results in two versions of ACTN3: a functional R allele and a null X allele. The homozygous genotype for the X allele (XX) is completely deficient in alpha-actinin 3.

It has been demonstrated that male and female elite sprint athletes have significantly higher frequencies of the R alleles than endurance athletes and sedentary controls (7). A study of elite and local black and white bodybuilders showed a significantly lower XX frequency in the bodybuilders compared to controls (8). Additionally, in a cycling study, it was found that subjects who were not ACTN3 deficient had greater peak power outputs and ventilatory thresholds than cyclists with the XX genotype (9).

So, we would assume that most top strength and power athletes need the active ACTN3 form to succeed, but they also need many other genetic, lifestyle and training factors. This is one example of not relying too much on the information of one gene – or putting all your eggs in one basket.

Genetics of gene: CYP1A2 (Cytochrome P450 A2)

The cytochrome p450 (CYP450) family of enzymes was first linked to drug metabolism in the 1970s. The amount of CYP450 enzymes available can determine the speed at which drugs are cleared from the body. Some drugs increase the speed of the enzymes, whereas others decrease the speed.

The CYP1A2 C allele is associated with lower CYP1A2 enzyme activity – CYP1A2 metabolises caffeine (by demethylation) and is also induced by smoking. Other drugs metabolised by this enzyme include theophylline, warfarin, and several antidepressants and antipsychotics. 

So, we know that carriers of the CYP1A2 C allele are slower at breaking down caffeine, especially if certain medications are also being consumed. Because caffeine is an excellent ergogenic aid for endurance performance and mental sharpness, many athletes take caffeine before performing.

Therefore, athletes with the CYP1A2 C allele must be more cautious of caffeine supplementation (10). Firstly, they should err on the low side of recommended dosages, and secondly, depending on the length of the competition, they could practice adjusting the time prior to the competition when they ingest the caffeine – if they take it too close to the event, caffeine’s effects may only kick in after the time when it was needed. Additionally, if they take too much, they could risk caffeine levels above the legal limit in their bloodstream.

On the other hand, those who metabolise caffeine quickly (CYP1A2 A allele carriers), will probably benefit by taking more of it and closer to the beginning of their event. If it is a long endurance event, it might also be worth them supplementing caffeine during the race.

Genetics of gene: PPARGC1A (Peroxisome Proliferator-Activated Receptor-Gamma Coactivator-1α)

PPARGC1A (otherwise known as PGC-1α) is involved in mitochondrial biogenesis, fatty acid oxidation, adipocyte differentiation, glucose utilisation, thermogenesis, angiogenesis and muscle fibre type conversion towards type I fibres. It is abundant in mitochondria, and the activation of PPARGC1A may mediate the initial phase of the exercise-induced adaptive increase in muscle mitochondria.

After nine months of training, individuals with the A allele in their PPARGC1A gene experienced lower increases in anaerobic threshold compared to individuals who were homozygous for the G allele (11). Additionally, those A-carrying individuals had less improvements in insulin sensitivity after the training programme.

Increasing evidence suggests that PGC-1α is also a powerful regulator of oxidative stress removal by increasing the expression of numerous antioxidant enzymes (12). Therefore, by controlling both the induction of mitochondrial metabolism and the removal of its oxidative by-products, PGC-1α should support oxidative metabolism and minimize the impact of oxidative stress on cell physiology. Additionally, high levels of PGC-1α result in elevated activity of Krebs cycle enzymes.

As shown in Figure 1, PGC-1α can be influenced by Nitric Oxide (NO), SIRT1, the so-called anti-ageing gene, Adenosine Mono Phosphate Kinase (AMPK), exercise and various dietary antioxidants and other nutrients.

 

Genetics of gene: EIF4G1 (Eukaryotic Translation Initiation Factor 4G1)

Overtraining syndrome, underperformance syndrome, chronic fatigue, fibromyalgia, adrenal fatigue: these are all terms that have become synonymous with high-level sport. At some point in heavy training, the body shows cracks and refuses to work at its previous standard. It seems that such syndromes may have a genetic connection.

Research in London (14) has revealed approximately 35 genes that may be linked to chronic fatigue syndrome. The mitochondrial gene EIF4G1 may be hijacked by some viruses, causing mitochondrial dysfunction and resulting fatigue. Another London study (15) compared levels of gene expression of the leukocytes of 25 healthy subjects with 25 chronic fatigue patients – they identified 15 genes that were up to four times as active in chronic fatigue patients compared to control subjects. The EIF4G1 gene has received the most attention in chronic fatigue patients, and its upregulation is consistent with a persistent viral infection such as Epstein Barr.

Further work needs to be done in this area, but overtraining and underperformance syndromes may be linked with some genetic influence.

Conclusions

The genetics of sport is now well beyond that of simple academic interest. There are some genes, like EIF4G1, that need further research before inclusion in a commercial test is possible, but there are others that are already extremely well-researched. As noted, it is important not to put too much emphasis on single genes and to always look for appropriate application and intervention of genetic information. Many genes are capable of influencing athletic performance, and there are several that I haven’t mentioned. For example, certain genes are involved in soft tissue injury and recovery from exercise and are particularly reliant on good nutrition: dietary collagen pre-cursers can support soft tissue repair, and anti-inflammatory nutrients and herbs can assist in recovery between sessions.