Introduction ! Endurance sports performance is associated with the interplay of several physiological factors, in- cluding: i) maximal oxygen uptake (V ˙ O 2max ); ii) the ability to sustain high workloads before lac- tate accumulates in the blood or the ventilation increases disproportionately, i.e., the ventilatory (VT)/respiratory compensation thresholds (RCT); and iii) the energetic efficiency of muscle output, which in the case of cycling can be expressed as gross mechanical efficiency (GE) (i.e., the ratio [× 100] of work accomplished • min –1 to energy expended • min –1 during a constant-load exercise bout) or delta efficiency (DE) (which is deter- mined from linear regression of the relationship between energy expended • min –1 and work ac- complished • min –1 during tests of gradually in- creasing loads) [1,2, 6,14]. Muscle efficiency has been less studied in the scientific literature than other endurance phenotype traits, though it may be a critical factor determining endurance per- formance [6]. The number of genes and markers with a possible association with one or more endurance pheno- type traits (i.e., V ˙ O 2max , VT, etc.) is growing each year, substantially due to the findings arising from the prestigious Genathlete study [20]. Although the human gene map for endurance performance phenotypes is gradually growing in complexity, progress is relatively slow in the field of genetics and sports performance compared to other research areas in genetics (pharmacoge- nomics, genetic bases of chronic diseases such as cancer or cardiovascular disease, etc.) [20]. Fur- ther, although several candidate genes have been proposed to explain individual differences in hu- man endurance phenotypic traits, particularly V ˙ O 2max , results are often conflicting and/or diffi- cult to extrapolate to actual competition per- formance. One potential source of controversy comes from combining endurance athletes from mixed sporting disciplines, thereby involving phenotypic heterogeneity, e.g., comparisons be- tween genotype frequencies of a given polymor- phism in athletes vs. sedentary controls. Dispar- Abstract ! We assessed the possible association between variants of the genes encoding for the angioten- sin-converting enzyme (ACE) and a-actinin-3 (ACTN3) (both individually and combined) and several endurance phenotypic traits, e.g., peak power output (PPO), ventilatory (VT) and respi- ratory compensation threshold (RCT), among others, in professional road cyclists and seden- tary controls (n = 46 each). We applied an ANCO- VA test using the aforementioned phenotype traits as dependent variables, ACE and/or ACTN3 genotype as the fixed (independent) factor and age and body mass as covariates. We only found a significant genotype effect with no concomi- tant covariate effect for ACTN3, with cyclists who were not a-actinin-3 deficient (RR + RX geno- types) having higher PPO and VT values than their XX counterparts (mean [SEM]: 7.4 (0.1) vs. 7.1 (0.1) W/kg, p =0.035; and 4.5 (0.1) vs. 4.3 (0.1) W/kg, p = 0.029, respectively). Cyclists with an “extreme” ACTN3 and ACE genotype combina- tion, i.e., most strength/power oriented (DD + RR/ RX), had higher RCT values than those with the “intermediate” combinations (II + RX/RR, p= 0.036; and DD + XX, p = .0004) but similar to those with the most endurance oriented geno- type (II + XX). No significant differences (p > 0.05) were found in controls. In summary, in world-class cyclists, we only found an associa- tion between ACTN3 genotypes and VT and PPO, and between ACTN3/ACE genotype combinations and RCT. Endurance Performance: Genes or Gene Combinations? Authors F. Gómez-Gallego 1 , C. Santiago 1 , M. González-Freire 1 , C. A. Muniesa 2 , M. Fernández del Valle 2 , M. Pérez 2 , C. Foster 3 , A. Lucia 2 Affiliations 1 Biomedical Laboratory, Universidad Europea de Madrid, Madrid, Spain 2 Exercise Physiology, Universidad Europea de Madrid, Madrid, Spain 3 Exercise and Sport Sciences, University of Wisconsin-Lacrosse, Lacrosse, Wisconsin, United States Key words l " ACTN3 l " ACE l " gross efficiency l " delta efficiency l " respiratory compensation threshold accepted after revision April 17, 2008 Bibliography DOI 10.1055/s-2008-1038677 Published online July 23, 2008 Int J Sports Med 2009; 30: 66 – 72 © Georg Thieme Verlag KG Stuttgart • New York • ISSN 0172-4622 Correspondence Prof. Alejandro Lucia Universidad Europea de Madrid Exercise Physiology Villaviciosa de Odón 28670 Madrid Spain Fax: + 34 9 16 16 82 65 alejandro.lucia@uem.es 66 Gómez-Gallego F et al. Endurance Performance: Genes… Int J Sports Med 2009; 30: 66 – 72 Genetics & Molecular Biology