Br J Sports Med 43:307-309 doi:10.1136/bjsm.2008.049809
  • Short report

Unique among unique. Is it genetically determined?

  1. M Gonzalez-Freire1,
  2. C Santiago1,
  3. Z Verde1,
  4. J I Lao2,
  5. J OIivan1,
  6. F Gómez-Gallego1,
  7. A Lucia1
  1. 1
    Universidad Europea de Madrid, Spain
  2. 2
    Sabiobbi, Madrid, Spain
  1. Dr Alejandro Lucia, Polideportivo Universidad Europea de Madrid Villaviciosa de Odón Madrid 28670, Spain: alejandro.lucia{at}
  • Accepted 14 July 2008
  • Published Online First 28 July 2008


The cross-country world championship is one of the best models to study characteristics needed to achieve top-level endurance athletic capacity. We report the genotype combination of a recent cross-country champion (12 km race) in polymorphisms of seven genes that are candidates to influence endurance phenotype traits (ACTN3, ACE, PPARGC1A, AMPD1, CKMM, GDF8 (myostatin) and HFE). His data were compared with those of eight other runners (world-class but not world champions). The only athlete with the genotype theoretically more suited to attaining world-class endurance running performance was the case study subject. A favourable genetic endowment, together with exceptional environmental factors (years of altitude living and training in this case), seems to be necessary to attain the highest possible level of running endurance performance.

The cross-country world championship (XCW) is one of the best models to study characteristics needed to achieve top-level endurance athletic capacity, including mainly artificial selection over a large genetic pool. This is in fact one of the few sporting events in which all continents and most main human ethnic groups are represented. We hypothesised that genetic polymorphisms that have been associated with better endurance at the population level would be relatively over-represented among the highly selected group of XCW winners. An exceptional environment (extremely demanding training loads over the years) plus the said genetic factors (allowing for very high training responsiveness or trainability) would result in competition excellence.

We report the case of the 2007 champion in the XCW (long race) with a very consistent competition performance during the last years (top two–four in three other editions and consistently top nine since 2003). He is an Eritrean (East African) runner who belongs to the Tigrigna ethnic group. He and the other subjects (see below), whom we recruited through personal contact with their coaches/managers, provided informed consent to be evaluated in our laboratory (Universidad Europea de Madrid, Spain) and to publish his biological data for scientific purposes. He is an altitude native (∼2500 m) who lived at altitude during childhood and currently lives and trains at 2500–3000 m during 4–5 months per year.

In i) this runner, ii) six runners of Caucasian (Spanish) origin (meeting the criteria of having won the Spanish XC championships (long race) at least once with excellent performances in the XCW, i.e., top 20 in ⩾ one edition) and iii) two other top-level African runners (one Eritrean (top seven at least once in the XCW long race) and one from Zimbabwe (top 16)), we determined genotypes of several genes that are candidates to influence endurance phenotype traits at baseline and/or in response to training (especially muscle efficiency, e.g., running economy (RE), a key determinant factor of endurance running performance1).

The polymorphisms of the genes we studied, together with a summary of their main potential roles, are listed below: i) R577X of the α-actinin-3 (ACTN3) gene (involved in muscles’ ability to produce fast contractions while avoiding damage originated by eccentric muscle contractions such as those involved in running)1 2; ii) I/D of the angiotensin-converting enzyme (ACE) gene (cardiovascular and skeletal muscle function, training response of muscle efficiency and hypertrophy3 4); iii) Gly482Ser of the peroxisome proliferator-activated receptor γ coactivator 1α (PPARGC1A) gene (mitochondrial biogenesis and skeletal muscle fibre-type conversion, i.e., II→I)5; iv) C34T of the skeletal muscle-specific isoform of AMP deaminase (AMPD1) gene (salvage of adenine nucleotides and regulation of muscle glycolysis during intense exercise)6; v) 985 bp/1170 bp of the muscle-specific creatine kinase (CKMM) gene (energy buffering in skeletal muscle fibres, tolerance to skeletal muscle damage)7; vi) K153R, E164K, P198A and I225T of the myostatin (growth and differentiation factor, GDF8) gene (muscle strength)810 and vii) H63D of the hereditary haemochromatosis (HFE) gene (iron storing capacity in response to iron supplementation with no deleterious health effects).11

During Winter–Spring 2004 (for African runners) and 2005 (for most Spanish runners), we extracted genomic DNA in all subjects from peripheral EDTA-treated anticoagulated blood (in the Exercise Physiology Laboratory (Universidad Europea de Madrid, Spain)) according to standard phenol/chloroform procedures followed by alcohol precipitation. Except for HFE and GDF8 sequencing (which was performed in Spring 2008), sequences corresponding to each mutation of the different genes were amplified by the polymerase chain reaction (PCR) in 2004–2005. The resulting PCR products were genotyped (in the Genetics Laboratory of Universidad Europea de Madrid, Spain) by single base extension (SBE) (HFE and GDF8), restriction fragment length polymorphisms (RFLP) (ACTN3, AMPD1, CKMM and PPARGC1A) or electrophoresis through agarose gel (ACE). To ensure proper internal control, for each genotype analysis we used positive and negative controls from different DNA aliquots which were previously genotyped with the same method. In addition, following recent recommendations for human genotype–phenotype association studies, which include “a subset of notable polymorphisms should be evaluated with a second technology that verifies the same result with excellent concordance”,12 ACTN3 and ACE genotyping was also performed in Spring 2008 in another genetics laboratory (Progenika, Parque Tecnológico de Zamudio, Spain) using a different methodology (oligonucleotide-based DNA microarray attaching oligonucleotide probes for the two genes to an amino-silanised glass using a spotting device).

Genotyping was performed specifically for research purposes based on the hypothesis that the aforementioned polymorphisms are candidate variants influencing endurance performance, i.e., the genotype data of the subjects were not previously analysed for other non-research purposes and as such were not presented a posteriori for the present paper. The researchers in charge of genotyping were totally blinded to the runners’ identities, i.e., blood samples were tracked solely with bar-coding and personal identities were only made available to the main study researcher who was not involved in actual genotyping.

Based on previous research data17 10 11 we hypothesised what could be an ideal genotype combination for an endurance runner, ie, among other capabilities, allowing his/her skeletal muscles to produce (i) high force and very fast contractions if needed (at the end of the race), (ii) highest possible outputs at the lowest oxygen cost (ie, high running economy (RE)), iii) to minimise muscle damage after hard running bouts, and iv) to maintain a good energetic status during intense exercise (table 1). Improved ventricular–vascular coupling (reduced after-load) and the ability to tolerate iron supplements are other potential advantages associated with the champion’s ideal genotype combination. In this regard, it is important to note that our approach was obviously not intended to provide a true test of the hypothesis that a unique combination of genetic and environmental factors contributes to the attainment of success in endurance running competitions. Rather, our goal was simply to provide additional supporting evidence (coming from an observation in a very small, yet remarkable group of competitors) for the potential role of several genetic variants that are candidates to influence top-level endurance running performance.

Table 1 Genotype combinations in the study subjects

Except for an initial problem in ACTN3 genotyping in one of the laboratories (due to a contamination problem in DNA probes which forced restarting of the whole sequencing process), no failures occurred in sample collection, DNA acquisition or genotyping procedures. Both ACE and ACTN3 results obtained by the two said laboratories were identical.

The case study subject had a theoretically favourable genotype at all loci tested (table 1). This would suggest that his success is partly attributable to (i) a unique genotype combination (possibly in the candidate genes studied, but also in many others), and ii) exceptional environmental factors: a demanding training regimen (∼150 km/week) plus chronic hypoxic exposure (>2500 m) during most of his life, including numerous training sessions. The rest of the runners, all very accomplished yet non-world champions, did not have the same genotype combination. Large cohort studies are nevertheless necessary to corroborate that the genotype combination of our case study subject is actually the most favourable combination for endurance running.

An alternative interpretation of the data reveals that, although the genotype combination of the world champion was different from that of the other runners, there are many people in the planet not exposed to such unique environmental factors yet with the same genotype combination (as many of the theoretically favourable variants we studied, eg, non α-actinin-3 deficient, are frequent in the overall population). Indeed, only a small fraction of the planet’s population enrols in rigorous, programmed sports training and thus in the artificial selection process that ends with the attainment of elite sports performance. It must be also kept in mind that numerous other contributors to the “complex trait” of being a world champion in distance running, e.g., lung capacity, joint mechanics or endorphin production among others, are likely not reducible to defined genetic polymorphisms.

While the potential contribution of numerous genetic variants (many of which remain to be identified and each with a small, yet significant contribution) must be kept in mind, exceptional environmental factors (e.g., years of demanding training under hypoxia) are also necessary to determine top-level endurance performance.

What is already known on this topic

Though numerous polymorphisms (e.g., in ACE, PPARGC1A or AMPD1 genes) are candidates to influence endurance exercise phenotype traits, little is known on what would be the ideal genotype combination in those attaining the highest competition level in endurance running, e.g., winners of the cross-country world championship (XCW).

What this study adds

While keeping in mind the need for large cohort studies, we reported what is the ideal genotype combination in an endurance running champion (male XCW winner) for the polymorphisms of the following seven genes: ACTN3, ACE, PPARGC1A, AMPD1, CKMM, GDF8 (myostatin) and HFE.


  • Funding: M Gonzalez-Freire is supported by the Fondo de Investigaciones Sanitarias (FI07/00189). This study was supported by a grant from Consejo Superior de Deportes (ref. 03/UPR10/07).

  • Competing interests: None.