ACTN3 Variants and Athletic Performance

The Health Outcome

Many genetic and environmental factors are likely to affect fitness and athletic ability. The 2002 Update of the Human Gene Map for Performance and Health-related Fitness Phenotypes reports 92 genes and quantitative trait loci (90 on the autosomes, 2 on the X chromosome) and 14 mitochrondrial genes shown to be related to physical performance of health-related phenotypes in at least one study (1).

The Finding

A study from Australia recently reported an association between variation in the alpha-actinin-3 ( ACTN3 ) gene R577 and athletic performance(2). The ACTN3 gene is part of a family of genes that code for actin-binding proteins known as alpha-actinins (3).  These proteins play a major role in the Z-line involved in anchoring the actin-containing thin filaments in skeletal muscle. ACTN3 is expressed only in type 2 muscle (fast-twitch) fibers while the ACTN2 isoform is found in all muscle fibers. A common nonsense mutation in ACTN3 (R577X) results in alpha-actin-3 deficiency that appears to be non-pathogenic and it is postulated that alpha-actinin-2 compensates for the deficiency. Homozygosity for the null allele (577XX) is estimated to be ~18% in Europeans.

The study investigators postulated that deficiency of alpha-actin-3 would reduce the performance of athletes involved in sprint/power events. To test this hypothesis, 436 unrelated white controls (150 blood donors, 71 healthy children from an unrelated study, and 215 healthy adults participating in a talent-identification program with the Australian Institute of Sport) and 429 elite white athletes were genotyped. The athletes were further subdivided in a blinded fashion into sprint/power athletes (107) and endurance athletes (194); 128 were not able to be classified and were excluded from the analyses. Chi-square analysis showed no significant allele or genotype frequency differences between athletes as a whole and controls; however, there was evidence of allele frequency variation when the athletes were divided into sprint/power and endurance groups and compared to controls as follows:

• Sprint athlete group had a lower frequency of the alpha-actinin-3 null genotype (6% vs 18%); no female sprint athletes had the null genotype
• Sprint athlete group had a higher frequency of the homozygous normal genotype (50% vs 30%) and a lower frequency of the heterozygous genotype (45% vs 52%)
• Endurance athlete group had a slightly higher frequency of the alpha-actinin-3 null genotype (24% vs 18%)
• In sprint and endurance groups allele frequencies deviated in opposite directions and were significantly different from each other in both males and females
• In female sprint and endurance groups there was evidence of genotype variation not explained by allele frequency differences 

From these findings, the researchers conclude that the normal ACTN3 allele (577R) confers an advantage for sprint/power athletic activities which is consistent with the known function and distribution of the gene product in skeletal muscle. They also postulate that the high frequency of 577XX genotype might be due to maintenance of the 577X allele because it could confer selective advantage under different environmental conditions than does the 577R allele. Based on the study findings, the authors also conclude that an individual is inherently predisposed to performance in either sprint/power or endurance activities and that genetic difference such as in ACTN3 may be useful predictors of athletic performance at the elite level.

Public Health Implications

Although interesting, the findings from this study are subject to limitations and are certainly not sufficient to assume a causal relation or warrant predictive testing. The association between a genetic variant and a health outcome or physical trait in a particular study can also be due to chance or to poor study design.  In this study the selection of subjects provides a potential source of bias. The criteria for classification of athletes (cases) into either the sprint/power or endurance group was not provided and approximately 30% of the sample was unable to be classified. If feasible, objective measures of muscle strength and endurance would be preferable; if not feasible, delineation of subjective criteria is needed. Additionally, the controls were not collected from the same source population as the cases and are a convenience sample from three different sources.  

Despite the study limitations, the findings are strengthened by their biologic plausibility. There is also a dose response in that the strength of the association increases with the number of variant alleles (e.g., homozygosity for 577R is more likely to be associated with sprint/power ability than heterozygosity) (Tables 1 and 2).  

The conclusions based on this single study are now being translated into the clinical arena in that a company will soon be marketing this genetic test as an indicator of athletic potential. The company reports that “this invention will greatly assist athletes and their trainers to maximise the potential of an athlete in their chosen sport, by helping to identify the event in which they will most likely be successful ”.(4)   Assuming that the distribution of types of athletes in this study is representative of any population of elite athletes, the clinical validity of the test can be estimated. The sensitivity for determining either type of athletic ability is less than 50%. Also, the predictive power of the test is low. For example, for about 18% of the population of elite athletes who are homozygous for the null allele (577XX), the positive predictive value for the endurance trait is high at 88%. However, for greater than 80% of this population who are not homozygous for this allele, the negative predictive value is about 40% (Table 3). The clinical validity of a test must be interpreted in the context of the intended use of the test. The estimated predictive values for elite athletes raise the question of whether the test would have additional value over and above other characteristics and qualities (e.g., factors such as sport preference and personal drive) that are already known to the athlete. However, if the test is marketed to the general population to identify superior athletes and steer them in a particular direction, then the predictive value will be even less because the prevalence of such athletes is so low. Statements by sports officials reported in the popular press indicate that the test's anticipated use might extend beyond those competing at the elite level although its uncertain predictive value is noted  e.g., “screening would only ever give an indication, albeit a potentially valuable one, as to a child's athletic promise”(5). 

Investigation of the association of this genetic variant and its interaction with other genes and environmental factors needs to be done in well-controlled studies. Even if the findings reported by Yang and colleagues are validated in further studies, a thorough assessment of the benefit(s) of the test as well as the ethical, legal, and social implications of it use need to be addressed before the test is marketed to the consumer (6-7). 

Supplementary Tables

References

1. Pérusse L et al. The human gene map for performance and health-related fitness phenotypes: the 2002 update. Medicine & Science in Sports & Exercise. 2003;35:1248-1264.
2. Yang N et al. ACTN3 genotype is associated with human elite athletic performance. American Journal of  Human Genetics. 2003;73:627-631. PubMed abstract  (last accessed 3/2007)
3. Mills MA et al. Differential expression of the actin-binding proteins, alpha-actinin-2 and -3, in different species: implications for the evolution of functional redundancy. Human Molecular Genetics. 2001;10:1335-1346.
4. Genetic Technologies. 2003. GTG Appointed to Commercialise New Gene Invention by University of Sydney . Accessed 10/02/2003 .
5. BBC News. Top sprinters may have key gene . Published 08/27/2003. (last accessed 3/2007)
6. Haga SB et al. Genomic profiling to promote a healthy lifestyle: not ready for prime time. Nature Genetics. 2003;34:347-350.
7. Burke W et al. Genetic test evaluation: information needs of clinicians, policy makers, and the public. American Journal of Epidemiology. 2002;156:311-318.

Provides link to non-governmental sites and does not necessarily represent the views of the Centers  for Disease Control and Prevention.