Colin N. Moran

Association analysis of the ACTN3 R577X polymorphism and complex quantitative body composition and performance phenotypes in adolescent Greeks.

The functional allele (577R) of ACTN3, which encodes human α-actinin-3, has been reported to be associated with elite athletic status and with response to resistance training, while the nonfunctional allele (577X) has been proposed as a candidate metabolically thrifty allele. In a study of 992 adolescent Greeks, we show that there is a significant association (P=0.003) between the ACTN3 R577X polymorphism and 40 m sprint time in males that accounts for 2.3% of phenotypic variance, with the 577R allele contributing to faster times in an additive manner. The R577X polymorphism is not associated with other power phenotypes related to 40 m sprint, nor with an endurance phenotype. Furthermore, the polymorphism is not associated with obesity-related phenotypes in our population, suggesting that the 577X allele is not a thrifty allele, and thus the persistence of this null allele must be explained in other terms.

ACTN3 genotype, athletic status, and life course physical capability: meta-analysis of the published literature and findings from nine studies

The ACTN3 R577X (rs1815739) genotype has been associated with athletic status and muscle phenotypes, although not consistently. Our objective was to conduct a meta‐analysis of the published literature on athletic status and investigate its associations with physical capability in several new population‐based studies. Relevant data were extracted from studies in the literature, comparing genotype frequencies between controls and sprint/power and endurance athletes. For life course physical capability, data were used from two studies of adolescents and seven studies in the Healthy Ageing across the Life Course (HALCyon) collaborative research program, involving individuals aged between 53 and 90+ years. We found evidence from the published literature to support the hypothesis that in Europeans the RR genotype is more common among sprint/power athletes compared with their controls. There is currently no evidence that the X allele is advantageous to endurance athleticism. We found no association between R577X and grip strength (P = 0.09, n = 7,672 in males; P = 0.90, n = 7,839 in females), standing balance, timed get up and go, or chair rises in our studies of physical capability. The ACTN3 R577X genotype is associated with sprint/power athletic status in Europeans, but does not appear to be associated with objective measures of physical capability in the general population. Hum Mutat 32:1–11, 2011.

Fat Oxidation, Fitness and Skeletal Muscle Expression of Oxidative/Lipid Metabolism Genes in South Asians: Implications for Insulin Resistance?

Background South Asians are more insulin resistant than Europeans, which cannot be fully explained by differences in adiposity. We investigated whether differences in oxidative capacity and capacity for fatty acid utilisation in South Asians might contribute, using a range of whole-body and skeletal muscle measures. Methodology/Principal Findings Twenty men of South Asian ethnic origin and 20 age and BMI-matched men of white European descent underwent exercise and metabolic testing and provided a muscle biopsy to determine expression of oxidative and lipid metabolism genes and of insulin signalling proteins. In analyses adjusted for age, BMI, fat mass and physical activity, South Asians, compared to Europeans, exhibited; reduced insulin sensitivity by 26% (p = 0.010); lower VO2max (40.6±6.6 vs 52.4±5.7 ml.kg−1.min−1, p = 0.001); and reduced fat oxidation during submaximal exercise at the same relative (3.77±2.02 vs 6.55±2.60 mg.kg−1.min−1 at 55% VO2max, p = 0.013), and absolute (3.46±2.20 vs 6.00±1.93 mg.kg−1.min−1 at 25 ml O2.kg−1.min−1, p = 0.021), exercise intensities. South Asians exhibited significantly higher skeletal muscle gene expression of CPT1A and FASN and significantly lower skeletal muscle protein expression of PI3K and PKB Ser473 phosphorylation. Fat oxidation during submaximal exercise and VO2max both correlated significantly with insulin sensitivity index and PKB Ser473 phosphorylation, with VO2max or fat oxidation during exercise explaining 10–13% of the variance in insulin sensitivity index, independent of age, body composition and physical activity. Conclusions/Significance These data indicate that reduced oxidative capacity and capacity for fatty acid utilisation at the whole body level are key features of the insulin resistant phenotype observed in South Asians, but that this is not the consequence of reduced skeletal muscle expression of oxidative and lipid metabolism genes.

FTO genotype and adiposity in children: physical activity levels influence the effect of the risk genotype in adolescent males

Studies of the fat mass and obesity-associated (FTO) gene provide compelling evidence of genetic variation in the general population that influences fat levels and obesity risk. Studies of the interaction between genetic and environmental factors such as physical activity (PA) will promote the understanding of how lifestyle can modulate genetic contributions to obesity. In this study, we investigated the effect of FTO genotype, and interactions with PA or energy intake, in young children and adolescents. In all, 1–5-year-old children from the Growth, Exercise and Nutrition Epidemiological Study in preSchoolers (GENESIS) study (N=1980) and 11–18-year-old Greek adolescents (N=949) were measured for adiposity-related phenotypes and genotyped at the FTO single-nucleotide polymorphism (SNP) marker, rs17817449. Adolescents were classified as physically active or inactive based on self-reported levels of PA. In adolescents, FTO genotype influenced weight (P=0.001) and BMI (P=0.007). There was also a significant SNP*PA*gender interaction (P=0.028) on BMI, which reflected the association between FTO genotype and BMI in males (P=0.016), but not females (P=0.15), and significant SNP*PA interaction in males (P=0.007), but not females (P=0.74). The FTO genotype effect was more pronounced in inactive than active males. Inactive males homozygous for the G allele had a mean BMI 3 kg/m2 higher than T carriers (P=0.008). In the GENESIS study, no significant association between FTO genotype and adiposity was found. The present findings highlight PA as an important factor modifying the effect of FTO genotype.

The associations of ACE polymorphisms with physical, physiological and skill parameters in adolescents

Genetic variation in the human Angiotensin I-Converting Enzyme (ACE) gene has been associated with many heritable traits, including physical performance. Herein we report the results of a study of several physical, physiological and skill parameters and lifestyle in 1027 teenage Greeks. We show that there is a strong association (P<0.001) between the ACE I/D (insertion/deletion) polymorphism and both handgrip strength and vertical jump in females, homozygotes for the I-allele exhibiting higher performance-related phenotype scores, accounting for up to 4.5% of the phenotypic variance. The association is best explained by a model in which the D-allele is dominant, with the mean phenotypic value in the I/D heterozygotes being close to that of the mean of the DD homozygotes. The association acts across the phenotype distribution in a classical polygenic manner. Other polymorphisms that define major ACE haplotypes in European populations (rs4424958, rs4311) show weaker associations with these performance-related phenotypes than does I/D. Similarly, diplotypes defined by these polymorphisms do not explain significantly larger amounts of the variance than I/D alone. As ACE I/D is the polymorphism most strongly associated with circulating ACE activity in European populations, we propose that the functional allelic differences that influence ACE activity also mediate the associations with the performance-related phenotypes studied here.

Plasma MicroRNA Levels Differ between Endurance and Strength Athletes

Aim MicroRNAs (miRNAs) are stable in the circulation and are likely to function in inter-organ communication during a variety of metabolic responses that involve changes in gene expression, including exercise training. However, it is unknown whether differences in circulating-miRNA (c-miRNA) levels are characteristic of training modality. Methods We investigated whether levels of candidate c-miRNAs differ between elite male athletes of two different training modalities (n = 10 per group) - endurance (END) and strength (STR) - and between these groups and untrained controls (CON; n = 10). Fasted, non-exercised, morning plasma samples were analysed for 14 c-miRNAs (miR-1, miR-16-2, miR-20a-1, miR-21, miR-93, miR-103a, miR-133a, miR-146a, miR-192, miR-206, miR-221, miR-222, miR-451, miR-499). Moreover, we investigated whether c-miRNA levels were associated with quantitative performance-related phenotypes within and between groups. Results miR-222 was present at different levels in the three participant groups (p = 0.028) with the highest levels being observed in END and the lowest in STR. A number of other c-miRNAs were present at higher levels in END than in STR (relative to STR, ± 1 SEM; miR-222: 1.94 fold (1.73-2.18), p = 0.011; miR-21: 1.56 fold (1.39-1.74), p = 0.013; miR-146a: 1.50 fold (1.38-1.64), p = 0.019; miR-221: 1.51 fold (1.34-1.70), p = 0.026). Regression analyses revealed several associations between candidate c-miRNA levels and strength-related performance measures before and after adjustment for muscle or fat mass, but not following adjustment for group. Conclusion Certain c-miRNAs (miR-222, miR-21, miR-146a and miR-221) differ between endurance- and resistance-trained athletes and thus have potential as useful biomarkers of exercise training and / or play a role in exercise mode-specific training adaptations. However, levels of these c-miRNAs are probably unrelated to muscle bulk or fat reserves.

Direct-to-consumer genetic testing for predicting sports performance and talent identification: Consensus statement.

The general consensus among sport and exercise genetics researchers is that genetic tests have no role to play in talent identification or the individualised prescription of training to maximise performance. Despite the lack of evidence, recent years have witnessed the rise of an emerging market of direct-to-consumer marketing (DTC) tests that claim to be able to identify childrens athletic talents. Targeted consumers include mainly coaches and parents. There is concern among the scientific community that the current level of knowledge is being misrepresented for commercial purposes. There remains a lack of universally accepted guidelines and legislation for DTC testing in relation to all forms of genetic testing and not just for talent identification. There is concern over the lack of clarity of information over which specific genes or variants are being tested and the almost universal lack of appropriate genetic counselling for the interpretation of the genetic data to consumers. Furthermore independent studies have identified issues relating to quality control by DTC laboratories with different results being reported from samples from the same individual. Consequently, in the current state of knowledge, no child or young athlete should be exposed to DTC genetic testing to define or alter training or for talent identification aimed at selecting gifted children or adolescents. Large scale collaborative projects, may help to develop a stronger scientific foundation on these issues in the future.

Y chromosome haplogroups of elite Ethiopian endurance runners

Favourable genetic endowment has been proposed as part of the explanation for the success of East African endurance athletes, but no evidence has yet been presented. The Y chromosome haplogroup distribution of elite Ethiopian athletes (n=62) was compared with that of the general Ethiopian population (n=95) and a control group from Arsi (a region producing a disproportionate number of athletes; n=85). Athletes belonged to three groups: marathon runners (M; n=23), 5–km to 10–km runners (5–10K; n=21) and other track and field athletes (TF; n=18). DNA was extracted from buccal swabs and haplogroups were assigned after the typing of binary markers in multiplexed minisequencing reactions. Frequency differences between groups were assessed by using contingency exact tests and showed that Y chromosome haplogroups are not distributed amongst elite Ethiopian endurance runners in the same proportions as in the general population, with statistically significant (P<0.05) differences being found in four of the individual haplogroups. The geographical origins and languages of the athletes and controls suggest that these differences are less likely to be a reflection of population structure and that Y chromosome haplogroups may play a significant role in determining Ethiopian endurance running success.

Developmental changes in adiposity in toddlers and preschoolers in the GENESIS study and associations with the ACE I/D polymorphism

Objectives:To investigate the relationship between the angiotensin I-converting enzyme 1 (ACE) I/D polymorphism and adiposity-related phenotypes in a large cohort of toddlers and preschoolers.Methods:Body composition measurements and DNA samples were obtained from 2102 Greek children aged 1–6 years, as part of a large-scale epidemiological study (GENESIS). All children were genotyped for the ACE I/D polymorphism and gender- and age-stratified statistical analyses were performed.Results:In girls aged 4–6 years, the D-allele was associated with higher measurements of body mass index (BMI) (P=0.018), waist (P=0.001) and upper arm (P=0.013) circumferences, genotype accounting for 2.5, 4 and 3% of the phenotypic variance, respectively. In boys, the D-allele showed strong associations with lower BMI (P=0.001) at the age of 1–2 years that explained 17% of the phenotypic variance and with larger suprailiac skinfold (P=0.008) at 3–4 years old that explained 2% of the variance. No other significant associations between the ACE I/D polymorphism and adiposity-related phenotypes were found. In girls, the age at which significant associations were revealed coincided with the age at which BMI was observed to increase after its developmental nadir, but this feature of the association was not observed in boys.Conclusions:The ACE I/D polymorphism is associated with developmental and physiological changes in adiposity-related traits during early childhood in a gender- and age-specific manner.

Human alpha-actinin-3 genotype association with exercise-induced muscle damage and the repeated-bout effect.

Alpha-actinin-3 (ACTN3) is an integral part of the Z line of the sarcomere. The ACTN3 R577X (rs1815739) polymorphism determines the presence or absence of functional ACTN3, which may influence the extent of exercise-induced muscle damage. This study aimed to compare the impact of, and recovery from, muscle-damaging eccentric exercise on subjects with or without functional ACTN3. Seventeen young men (20-33 years old), homozygous for the R (n = 9) or X (n = 8) alleles, performed two bouts of stretch-shortening exercise (50 drop jumps) two weeks apart. Muscle soreness, plasma creatine kinase (CK) activity, jump height, maximal voluntary isometric torque (MVC), peak concentric isokinetic torque (IT), and electrically stimulated knee extension torques at 20 and 100 Hz were measured at baseline and at a number of time points up to 14 days after each bout. There were no significant baseline differences between the groups. However, significant time point × genotype interactions were observed for MVC (p = 0.021) and IT (p = 0.011) for the immediate effect of eccentric exercise in bout 1. The RR group showed greater voluntary force decrements (RR vs. XX: MVC, -33.3% vs. -24.5%; IT, -35.9% vs. -23.2%) and slower recovery. A repeated-bout effect was clearly observed, but there were no differences by genotype group. The ACTN3 genotype modulates the response of muscle function to plyometric jumping exercise, although the differences are modest. The ACTN3 genotype does not influence the clearly observed repeated-bout effect; however, XX homozygotes recover baseline voluntary torque values faster and thus may be able to undertake more frequent training sessions.