Nico Fontova

            Hard work and talent are two central components to athletic performance. It is crucial for a world-class athlete to be laser-focused committed to improvement, but hard work alone will not determine success. Whether we like it or not, talent—or genetics—influences athletics, but how exactly does it do it?

            There are over 150 genes found to be associated with athletic performance, but most do not have a large enough or statistically significant effect. Two genes in particular play a larger role in athletic performance and building certain types of athletes: ACTN3 (on chromosome 11) and ACE (chromosome 17). The ACTN3 gene creates alpha-actin-3, a protein which is part of the composition of fast twitch muscle fiber.¹ Fast twitch muscle fiber is one of two fibers in muscle. It can contract very quickly but also tires quickly and is key to our ability to sprint. Slow twitch fiber is the other; it contracts slowly but has much more endurance.¹ The mutation impacting ACTN3 is a SNP (a change of one base to another in the DNA sequence) which changes an amino acid into a stop codon, halting or entirely stopping alpha-actin production. This mutation is shorthanded with an X (for the premature stop) and the normal version is written as an R (for arginine, the original amino acid). Homozygous individuals are RR or XX, while heterozygotes are RX. XX individuals completely lack production of the protein, and therefore much less fast twitch muscle fiber. The XX allele is common in endurance athletes, while the RR and RX alleles are more common in short distance sprinters. The ACE gene codes for a protein which primarily regulates blood pressure, but also influences muscle function in an unclear way. The mutation in this case is an insertion called ACE-I, which is prominent in endurance athletes. ACE-D is the allele without the insertion, and DD and ID athletes are more likely to be sprinters.^1,3 These are the genes the influence athletic ability, and it is clear that being RR is more beneficial to sprinters, but is being an XX homozygote give you an advantage in endurance events? And if so, can people use genetic testing to determine their endurance ability?

            Genetic testing for ACTN3 and ACE mutations could possibly be an indicator of your athleticism and could be used to identify future sprinting or endurance talent in young people. 23andMe tests for both genes, so a SNP Chip would be the recommended test, but using these tests as absolute evidence for endurance ability is risky. 

• A University of Bristol study found the ACTN3 R allele to be associated with sprint performance in Europeans but did not find the X allele to improve endurance ability.⁴
• Another study found that only 20% of elite North American and European distance runners studied were XX homozygous, which is slightly higher than the control group at 17.5%.⁵
• There clearly is some benefit with the genes, however, as a Swedish study found that only three out of 46 Spanish distance runners tested had a perfect genotypic profile for endurance (including ACE-I and ACTN3-X), but they were among the best in the world.⁶             

XX homozygotes seem to have a slight advantage in endurance events (in that they are the best of the best in the Swedish study), but it is not a large or possibly notable advantage. Testing for these genes is clearly helpful in determining muscle performance, but they cannot predict someone’s proficiency in a sport by themselves, which could be unethical if taken too far.

            This trait does cross many ethical lines, except for possibly using the test to select children and train children from a young age for certain disciplines. Both ACE and ACTN3 are not the sole predictors of athletic performance, however, so making a child a distance runner because he is II or XX would be wrong; it is important for someone to do what they like and not necessarily what they would be genetically proficient in. Many other factors play into athletic ability including a healthy training environment and eagerness to improve, which may not be present if someone is being forced to train because of genetics. An X or I positive test would affect a sprinter more because they would have less fast twitch muscle fiber in their bodies than others and be at an actual and proven disadvantage. One could use testing to see if they would be good short distance athletes, but most people have the R alleles that account for sprinting ability (around 20%-100% of each studied ethnic group in SNPedia), suggesting that the test is really only useful in current sprinters to see if they are at a genetic disadvantage by being RX.² This test can be used to measure athletic ability, but a VO₂ Max test (a test of the max volume of oxygen the body can use under stress) would be much more useful in determining current athletic ability, while genetic testing could determine potential ability.

            If you test positive for the I or X alleles, maybe you should try your hand in endurance running, or if you already run, feel reassured in your choice, but don’t sweat it too much (unless you plan on being a world class 100 meter runner) because plenty of elite distance runners are RR or RX, and athletic ability is about more than just two genes.^5,6 In my opinion, parents should not test their children specifically for this gene or use the results to predict anything because there are many other factors contributing to athletic ability, and the evidence is not solid enough to prove that someone has talent for endurance event because of these genes. ACTN3 and ACE are indicators of how fast you can move, but they are not the whole story and certainly should not be treated as such.

References

1. Is Athletic Performance Determined by Genetics?. U.S. National Library of Medicine Web Site. https://ghr.nlm.nih.gov/primer/traits/athleticperformance. Updated November 12, 2019. Accessed November 14, 2019.

1. Rs1815739. SNPedia Web Site. https://www.snpedia.com/index.php/Rs1815739. Updated December 6, 2018. Accessed November 14, 2019.

1. Rs1799752. SNPedia Web Site. https://www.snpedia.com/index.php/Rs1799752. Updated January 6, 2018. Accessed November 14, 2019.

1. Alfred T, Ben-Shlomo Y, Cooper R, et al. ACTN3 genotype, athletic status, and life course physical capability: meta-analysis of the published literature and findings from nine studies. NCBI, 2011; Abstract. https://www.ncbi.nlm.nih.gov/pubmed/21542061?dopt=Abstract. Accessed November 14, 2019.

1. Döring FE, Onur S, Geisen U, et al. ACTN3 R577X and other polymorphisms are not associated with elite endurance athlete status in the Genathlete study. NCBI, 2010; Abstract. https://www.ncbi.nlm.nih.gov/pubmed/20845221?dopt=Abstract. Accessed November 14, 2019.

1. Ruiz JR, Gómez-Gallego F, Santiago C, et al. Is there an optimum endurance polygenic profile? NCBI, 2009; Abstract. https://www.ncbi.nlm.nih.gov/pubmed/19237423?dopt=Abstract. Accessed November 14, 2019.

Marfan syndrome is a genetic disease that affects the body’s connective tissue. People with the disease tend to be extremely tall and slender. This disease affects about 1 in every 5,000 people [1]. Marfan syndrome is typically caused by a mutation in the FBN1 gene which affects the way in which the protein fibrillin-1 is made. The production of the protein is enhanced and the surplus in fibrillin-1 is what harms the connective tissue, ultimately causing problems all over the body. Because Marfan syndrome causes complications throughout the body— such as in the heart, bones and joints, lungs, and nervous system— it makes sense that the FBN1 gene variation is what causes the disease [2].

[7]

Why and How to Test

            Testing for Marfan syndrome is very important if you think there might be a chance that you have it. This is due to the fact that even if the symptoms are not always life threatening, they are detrimental to your way of life. If you find out that they are a result of Marfan syndrome, you can be more cognizant of the way you go about life so that you can live up to the normal life expectancy that the disease usually entails. For example, having Marfan syndrome would make it dangerous to play contact sports, both because of the brittleness of your bones and the higher risk you have for heart enlargement and heart failure as a result of that. The most effective and efficient form of genetic testing for Marfan syndrome is single gene DNA sequencing, as the disease is typically a product of a variation in the FBN1 gene. This is the case for up to 90% of the time. If the result of the test is negative, it might be helpful to do the same DNA sequencing for TGFBR1 and TGFBR2. If the aforementioned complications are present and testing is positive for a variation in any of these genes, then it is highly likely that someone has Marfan syndrome [3]. But if there are no symptoms present, then there is a chance that the person has another disease. There is a 50% chance that a parent with the disease will pass it on to their offspring, so it is important to have as many family members as possible test [1].

Scientific Risks of Testing

            Having a genetic variation in the FBN1 gene usually causes some sort of condition that is paired with Marfan syndrome, such as the common variant rs12916536 leading to adolescent scoliosis [4]. However, testing for this gene is not always straightforward. For example, other variations of the gene can be linked to ectopia lentis syndrome, Weill-Marchesani syndrome, Shprintzen-Goldberg syndrome and neonatal progeroid syndrome [5]. Because of that, it is important to test multiple family members if there is a discovered variant in the FBN1 gene. Some of these gene changes could actually be polymorphisms, which are not likely to cause Marfan syndrome [5], so the risk of someone having a variation in the gene to also have Marfan syndrome is not a certainty, but not having that variation does mean that one does not have the disease.

Ethical Considerations

            Most of the ethical questions regarding genetic testing used for Marfan syndrome is meant to question if genetic testing is even the best method to determine if one has Marfan syndrome. First of all, the cost might not be worth it because of the obvious physical characteristics of one with Marfan syndrome. As a child works through adolescence, they eventually would be able to notice their unusually long limbs and fingers and would likely have other abnormalities common for the disease. While that might not be indicative of anything other than just being tall and skinny, there are enough complications with the body caused by Marfan syndrome that would pile up and ultimately cause worry. But even still, they would have to test in some manner to be sure.

Another reason why a DNA sequencing might not be the best option is that there are other tests that one can have, such as an EKG, cardio ultrasound, cardiac MRI, or CT scan. These are the best ways to see abnormalities with the heart, blood vessels, spine, and skeletal system. These tests however are typically more expensive than the genetic test, which is usually around $2,000 [5]. However, being able to see the plethora of complications through these medical examinations seems to be more effective than the genetic test, as variations found in the test might not prove someone has Marfan syndrome. People who take the genetic test would end up having to pay north of $2,000 more for a different test to get complete accuracy.

There also come the behavioral and psychological effects that come with knowing you have Marfan syndrome. Initially, there are feelings of denial, anger, and depression, which come with many diseases. But accepting that you or someone close has the disease means living a different way of life. For example, it is important to stay out of active sports and all activities that put someone at risk for severe injury. Also, people affected must come to terms with the idea that they look different than others and that they would in some cases need special protection. Finding the balance of protecting yourself or your child while still being as involved in activity as possible will alleviate some of the frustration with the way of life [6].

Questions to Ask Before Getting the Test

• If someone in the family has already tested positive, what are the chances that a child also tests positive? Children have a 50% chance of having the disease if one parent does. For more extended family, the chances vary as different parents come into play.
• What should be the plan if someone tests positive? The first thing to consider if someone tests positive is whether or not they want to participate in further screenings. If the cost of that isn’t worth it, then someone who tests positive should at least act as though they do have the disease, especially if they possess some of the bodily complications.
• What types of environmental factors should they consider changing if they test positive? Someone who tests positive should most certainly continue to stay active, but to a much lesser degree. Active sports and heavy lifting are highly dangerous to someone with Marfan syndrome, but it is absurd to completely remove physical activity from someone’s life.

Ultimately, a certain level of concern that you might have Marfan syndrome would make it worth it to get tested in some manner, whether it be genetic testing, medical screening, or both. Knowledge that you might have to change your lifestyle is scary, but it beats the likely alternative of dying from the complications of Marfan syndrome when you weren’t aware you had it.

References

1. “What Is Marfan Syndrome?” The Marfan Foundation, 3 Oct. 2018, www.marfan.org/about/marfan.
2. “Marfan Syndrome.” National Center for Biotechnology Information, U.S. National Library of Medicine, www.ncbi.nlm.nih.gov/gtr/conditions/C0024796/.
3. “Marfan Syndrome – FBN1 Gene.” National Center for Biotechnology Information, U.S. National Library of Medicine, www.ncbi.nlm.nih.gov/gtr/tests/502890/.
4. Sheng, Fei, et al. “New Evidence Supporting the Role of FBN1 in the Development of Adolescent Idiopathic Scoliosis.” National Center for Biotechnology Information, U.S. National Library of Medicine, 15 Feb. 2019, www.ncbi.nlm.nih.gov/pubmed/30044367.
5. “Marfan Syndrome Diagnosis and Tests.” Cleveland Clinic, 3 May 2019, my.clevelandclinic.org/health/diseases/17209-marfan-syndrome/diagnosis-and-tests.
6. Bennett, Robin L., and Meinhard Robinow. “Marfan Syndrome.” University of Washington Orthopedics and Sports Medicine, orthop.washington.edu/patient-care/articles/arthritis/marfan-syndrome.html.
7. Zink, William P., “Marfan Syndrome.” August 2015, http://zinkmd.com/portfolio/amet-sollicitudin.