Association analysis of ACE and ACTN3 in elite Caucasian and East Asian swimmers.

PURPOSE: Polymorphic variation in the angiotensin-converting enzyme (ACE) and α-actinin-3 (ACTN3) genes has been reported to be associated with endurance and/or power-related human performance. Our aim was to investigate whether polymorphisms in ACE and ACTN3 are associated with elite swimmer status in Caucasian and East Asian populations. METHODS: ACE I/D and ACTN3 R577X genotyping was carried out for 200 elite Caucasian swimmers from European, Commonwealth, Russian, and American cohorts (short and middle distance, ≤400 m, n = 130; long distance, >400 m, n = 70) and 326 elite Japanese and Taiwanese swimmers (short distance, ≤100 m, n = 166; middle distance, 200-400 m, n = 160). Genetic associations were evaluated by logistic regression and other tests accommodating multiple testing adjustment. RESULTS: ACE I/D was associated with swimmer status in Caucasians, with the D allele being overrepresented in short-and-middle-distance swimmers under both additive and I-allele-dominant models (permutation test P = 0.003 and P = 0.0005, respectively). ACE I/D was also associated with swimmer status in East Asians. In this group, however, the I allele was overrepresented in the short-distance swimmer group (permutation test P = 0.041 and P = 0.0098 under the additive and the D-allele-dominant models, respectively). ACTN3 R577X was not significantly associated with swimmer status in either Caucasians or East Asians. CONCLUSIONS: ACE I/D associations were observed in these elite swimmer cohorts, with different risk alleles responsible for the associations in swimmers of different ethnicities. The functional ACTN3 R577X polymorphism did not show any significant association with elite swimmer status, despite numerous previous reports of associations with "power/sprint" performance in other sports.

Genes, athlete status and training -- An overview.

Significant data confirming the influence of genes on human physical performance and elite athlete status have been accumulated in recent years. Research of gene variants that may explain differences in physical capabilities and training-induced effects between subjects is widely carried out. In this review, the findings of genetic studies investigating DNA polymorphisms and their association with elite athlete status and training responses are reported. A literature search revealed that at least 36 genetic markers (located within 20 autosomal genes, mitochondrial DNA and Y-chromosome) are linked to elite athlete status and 39 genetic markers (located within 19 genes and mitochondrial DNA) may explain, in part, an interindividual variability of physical performance characteristics in response to endurance/strength training. Although more replication studies are needed, the preliminary data suggest an opportunity to use some of these genetic markers in an individually tailored prescription of lifestyle/exercise for health and sports performance.

The combined impact of metabolic gene polymorphisms on elite endurance athlete status and related phenotypes.

Endurance performance is a complex phenotype subject to the influence of both environmental and genetic factors. Although the last decade has seen a variety of specific genetic factors proposed, many in metabolic pathways, each is likely to make a limited contribution to an 'elite' phenotype: it seems more likely that such status depends on the simultaneous presence of multiple such variants. The aim of the study was to investigate individually and in combination the association of common metabolic gene polymorphisms with endurance athlete status, the proportion of slow-twitch muscle fibers and maximal oxygen consumption. A total of 1,423 Russian athletes and 1,132 controls were genotyped for 15 gene polymorphisms, of which most were previously reported to be associated with athlete status or related intermediate phenotypes. Muscle fiber composition of m. vastus lateralis in 45 healthy men was determined by immunohistochemistry. Maximal oxygen consumption of 50 male rowers of national competitive standard was determined during an incremental test to exhaustion on a rowing ergometer. Ten 'endurance alleles' (NFATC4 Gly160, PPARA rs4253778 G, PPARD rs2016520 C, PPARGC1A Gly482, PPARGC1B 203Pro, PPP3R1 promoter 5I, TFAM 12Thr, UCP2 55Val, UCP3 rs1800849 T and VEGFA rs2010963 C) were first identified showing discrete associations with elite endurance athlete status. Next, to assess the combined impact of all 10 gene polymorphisms, all athletes were classified according to the number of 'endurance' alleles they possessed. The proportion of subjects with a high (≥9) number of 'endurance' alleles was greater in the best endurance athletes compared with controls (85.7 vs. 37.8%, P = 7.6 × 10(-6)). The number of 'endurance' alleles was shown to be positively correlated (r = 0.50; P = 4.0 × 10(-4)) with the proportion of fatigue-resistant slow-twitch fibers, and with maximal oxygen consumption (r = 0.46; P = 7.0 × 10(-4)). These data suggest that the likelihood of becoming an elite endurance athlete depends on the carriage of a high number of endurance-related alleles.

Association of the VEGFR2 gene His472Gln polymorphism with endurance-related phenotypes.

Vascular endothelial growth factor receptor 2 (VEGFR2) is essential to induce the full spectrum of VEGF angiogenic responses to aerobic training. In the present study, we examined the impact of the functional His472Gln polymorphism of the VEGFR2 gene on elite athlete status, endurance performance and muscle fibre type composition. Four hundred and seventy-one Russian athletes were prospectively stratified into four groups according to event duration, distance and type of activity, covering a spectrum from the more endurance-oriented to the more power-oriented. VEGFR2 genotype and allele frequencies were compared to 603 controls. To examine the association between VEGFR2 genotype and fibre type composition, vastus lateralis muscle biopsies were obtained from 45 physically active healthy men and 23 all-round speed skaters. In addition, 76 competitive rowers performed incremental endurance exercise to allow analysis of genotype associations with exercise responses. We found that the frequency of the VEGFR2 472Gln allele was significantly higher in endurance-oriented athletes compared to controls (36.8 vs. 27.4%, P = 0.0006). Relative VO(2max) was significantly greater in the VEGFR2 472Gln allele carriers compared with the His/His homozygotes of the sub-elite female rower group only. Genotype-specific differences were found for the proportion of slow-twitch fibres in both athletes and controls, which was approximately 10.1 and approximately 7.4% higher in the His/Gln and Gln/Gln genotypes than in the His/His genotype group, respectively. In conclusion, we have shown for the first time that variation in the VEGFR2 gene is associated with elite athlete status, endurance performance of female rowers and muscle fibre type composition.

Association of the ACTN3 R577X polymorphism with power athlete status in Russians.

The alpha-actinin-3 (ACTN3) gene encodes a Z-disc structural protein which is found only in fast glycolytic muscle fibers. A common nonsense polymorphism in codon 577 of the ACTN3 gene (R577X) results in alpha-actinin-3 deficiency in XX homozygotes. Previous reports have shown a lower proportion of the ACTN3 XX genotype in power-oriented athletes compared to the general population. In the present study we tested whether XX genotype was under-represented in Russian power-oriented athletes. The study involved 486 Russian power-oriented athletes of regional or national competitive standard. ACTN3 genotype and allele frequencies were compared to 1,197 controls. The frequencies of the ACTN3 XX genotype (6.4 vs. 14.2%; P < 0.0001) and X allele (33.3 vs. 38.7%; P = 0.004) were significantly lower in power-oriented athletes compared to controls. Furthermore, the lowest (3.4%) frequency of the ACTN3 XX genotype was found in a group of highly elite athletes, supporting the hypothesis that the presence of alpha-actinin-3 has a beneficial effect on the function of skeletal muscle in generating forceful contractions at high velocity. In conclusion, ACTN3 R577X polymorphism was associated with power athlete status in Russians.

PPARalpha gene variation and physical performance in Russian athletes.

Peroxisome proliferator-activated receptor alpha (PPARalpha) regulates genes responsible for skeletal and heart muscle fatty acid oxidation. Previous studies have shown that the PPARalpha intron 7 G/C polymorphism was associated with left ventricular growth in response to exercise. We speculated that GG homozygotes should be more prevalent within a group of endurance-oriented athletes, have normal fatty acid metabolism, and increased percentages of slow-twitch fibers. We have tested this hypothesis in the study of a mixed cohort of 786 Russian athletes in 13 different sporting disciplines prospectively stratified by performance (endurance-oriented athletes, power-oriented athletes and athletes with mixed endurance/power activity). PPARalpha intron 7 genotype and allele frequencies were compared to 1,242 controls. We found an increasing linear trend of C allele with increasing anaerobic component of physical performance (P=0.029). GG genotype frequencies in endurance-oriented and power-oriented athletes were 80.3 and 50.6%, respectively, and were significantly (P<0.0001) different compared to controls (70.0%). To examine the association between PPARalpha gene variant and fiber type composition, muscle biopsies from m. vastus lateralis were obtained and analyzed in 40 young men. GG homozygotes (n=25) had significantly (P=0.003) higher percentages of slow-twitch fibers (55.5+/-2.0 vs 38.5+/-2.3%) than CC homozygotes (n=4). In conclusion, PPARalpha intron 7 G/C polymorphism was associated with physical performance in Russian athletes, and this may be explained, in part, by the association between PPARalpha genotype and muscle fiber type composition.