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1.  ACTN3 genotype, athletic status and lifecourse physical capability: meta-analysis of the published literature and findings from nine studies 
Human mutation  2011;32(9):1008-1018.
The ACTN3 R577X (rs1815739) genotype has been associated with athletic status and muscle phenotypes, though 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 lifecourse physical capability, data were used from two studies of adolescents and seven studies in the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, 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-value=0.09, n=7672 in males; p-value=0.90, n=7839 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.
PMCID: PMC3174315  PMID: 21542061
ACTN3; Actinin-3; athlete; aging; SNP; grip strength
2.  The ACTN3 R577X Polymorphism across Three Groups of Elite Male European Athletes 
PLoS ONE  2012;7(8):e43132.
The ACTN3 R577X polymorphism (rs1815739) is a strong candidate to influence elite athletic performance. Yet, controversy exists in the literature owing to between-studies differences in the ethnic background and sample size of the cohorts, the latter being usually low, which makes comparisons difficult. In this case:control genetic study we determined the association between elite athletic status and the ACTN3 R577X polymorphism within three cohorts of European Caucasian men, i.e. Spanish, Polish and Russian [633 cases (278 elite endurance and 355 power athletes), and 808 non-athletic controls]. The odds ratio (OR) of a power athlete harbouring the XX versus the RR genotype compared with sedentary controls was 0.54 [95% confidence interval (CI): 0.34–0.48; P = 0.006]. We also observed that the OR of an endurance athlete having the XX versus the RR genotype compared with power athletes was 1.88 (95%CI: 1.07–3.31; P = 0.028). In endurance athletes, the OR of a “world-class” competitor having the XX genotype versus the RR+RX genotype was 3.74 (95%CI: 1.08–12.94; P = 0.038) compared with those of a lower (“national”) competition level. No association (P>0.1) was noted between the ACTN3 R577X polymorphism and competition level (world-class versus national-level) in power athletes. Our data provide comprehensive support for the influence of the ACTN3 R577X polymorphism on elite athletic performance.
PMCID: PMC3420864  PMID: 22916217
3.  The Association of Sport Performance with ACE and ACTN3 Genetic Polymorphisms: A Systematic Review and Meta-Analysis 
PLoS ONE  2013;8(1):e54685.
Genetic polymorphism is suggested to be associated with human physical performance. The angiotensin I-converting enzyme insertion/deletion (ACE I/D) polymorphism and the α-actinin-3 gene (ACTN3) R577X polymorphism have been most widely studied for such association analysis. However, the findings are frequently heterogeneous. We aim to summarize the associations of ACE I/D and ACTN3 R577X with sport performance by means of meta-analysis.
We systematically reviewed and quantitatively summarized published studies, until October 31, 2012, on relationship between ACE/ACTN3 genetic polymorphisms and sports performance, respectively.
A total of 366 articles on ACE and 88 articles on ACTN3 were achieved by literature search. A significant association was found for ACE II genotype compared to D allele carriage (DD+ID) with increased possibility of physical performance (OR, 1.23; 95% CI, 1.05–1.45). With respect to sport discipline, the II genotype was found to be associated with performance in endurance athletes (OR, 1.35; 95% CI, 1.17–1.55). On the other hand, no significant association was observed for ACTN3 RR genotype as compared to X allele carriage (XX+RX) (OR, 1.03; 95% CI, 0.92–1.15). However, when restricted the analyses to power events, a significant association was observed (OR, 1.21; 95% CI, 1.03–1.42).
Our results provide more solid evidence for the associations between ACE II genotype and endurance events and between ACTN3 R allele and power events. The findings suggest that the genetic profiles might influence human physical performance.
PMCID: PMC3554644  PMID: 23358679
4.  Interaction Between ACE I/D and ACTN3 R557X Polymorphisms in Polish Competitive Swimmers 
Journal of Human Kinetics  2014;42:127-136.
We hypothesized that the ACE ID / ACTN3 R577X genotype combination was associated with sprint and endurance performance. Therefore, the purpose of the present study was to determine the interaction between both ACE ID and ACTN3 R577X polymorphisms and sprint and endurance performance in swimmers. Genomic DNA was extracted from oral epithelial cells using GenElute Mammalian Genomic DNA Miniprep Kit (Sigma, Germany). All samples were genotyped using a real-time poly- merase chain reaction. The ACE I/D and the ACTN3 R577X genotype frequencies met Hardy-Weinberg expectations in both swimmers and controls. When the two swimmer groups, long distance swimmers (LDS) and short distance swimmers (SDS), were compared with control subjects in a single test, a significant association was found only for the ACE polymorphism, but not for ACTN3. Additionally, four ACE/ACTN3 combined genotypes (ID/RX, ID/XX, II/RX and II/XX) were statistically significant for the LDS versus Control comparison, but none for the SDS versus Control comparison. The ACE I/D and the ACTN3 R577X polymorphisms did not show any association with sprint swimming, taken individually or in combination. In spite of numerous previous reports of associations with athletic status or sprint performance in other sports, the ACTN3 R577X polymorphism, in contrast to ACE I/D, was not significantly associated with elite swimming status when considered individually. However, the combined analysis of the two loci suggests that the co-occurrence of the ACE I and ACTN3 X alleles may be beneficial to swimmers who compete in long distance races.
PMCID: PMC4234751  PMID: 25414746
ACE; ACTN3; gene polymorphism; swimming
5.  Prevalence of ACTN3 (the athlete gene) R577X polymorphism in Iranian population 
Ability of athletes in speed or endurance contests somehow is determined by inherited muscle fiber types. One of the important genes involved in sport genetics is ACTN3 that is located on chromosome 11q13-q14 and encodes α-actinin-3, which belongs to highly conserved family of α-actinin proteins. Genetic analysis of α-actinin-3 gene has showed a polymorphism R577X (rs1815739), which results in premature stop codon and leads to non functional α-actnin-3 protein. ACTN3 genotype can contribute to the performance in elite and endurance activities.
R577X polymorphism replaces arginine by stop codon. Individuals homozygous for R577 have full copy of α-actinin-3 and elite and power sprint athletes show significantly higher frequency of 577R allele. In the other hand, some studies represented that X allele have high level of frequency in endurance athletes. However, this data remains controversial Since there is no information about the frequency of ACTN3 genotype in our population therefore as the first step it is essential to determine the genetic background of Iranian population. The objective of this study was to genotype normal Iranian individuals to determine the prevalence of each allele in our population.
We used PCR-RFLP method for genotyping 210 normal individuals.
Total of 210 Iranian normal individuals for distribution of R577X and R alleles were genotyped. The different genotypes were as follow; 24% RR (50/210), 65%RX (136/210) and 11%XX (24/210), with allelic distribution of 0.56 and 0.44 for 577R and 577X alleles of ACTN3.
This allelic distribution for Iranian's is more close to Caucasian population, which is concurrent with the route of ancient human's migration from Iran Plateau toward Europe.
Our results showed no different patterns of allelic distribution among female and males, which was the same in other studies too, although some differences has been reported in the studies on athletes population.
PMCID: PMC3518978  PMID: 23285413
Sport Genetics; ACTN3; Iran
6.  Association of the ACTN3 R577X Polymorphism in Polish Power-Orientated Athletes 
Journal of Human Kinetics  2011;28:55-61.
Alpha-actinins are an ancient family of actin-binding proteins that play structural and regulatory roles in cytoskeletal organization. In skeletal muscle, α-actinin-3 protein is an important structural component of the Z disc, where it anchors actin thin filaments, helping to maintain the myofibrillar array. A common nonsense polymorphism in codon 577 of the ACTN3 gene (R577X) results in α-actinin-3 deficiency in XX homozygotes. Based on knowledge about the role of ACTN3 R557X polymorphism in skeletal muscle function, we postulated that the genetic polymorphism of ACTN3 could also improve sprint and power ability.
We compared genotypic and allelic frequencies of the ACTN3 R557X polymorphism in two groups of men of the same Caucasian descent: 158 power-orientated athletes and 254 volunteers not involved in competitive sport.
The genotype distribution in the group of power-oriented athletes showed significant differences (P=0.008) compared to controls. However, among the investigated subgroups of athletes, only the difference of ACTN3 R577X genotype between sprinters and controls reached statistical significance (P=0.041). The frequencies of the ACTN3 577X allele (30.69% vs. 40.35%; P=0.005) were significantly different in all athletes compared to controls.
Our results support the hypothesis that the ACTN3 577XX allele may have some beneficial effect on sprint-power performance, because the ACTN3 XX genotype is significantly reduced in Polish power-oriented athletes compared to controls. This finding seems to be in agreement with previously reported case-control studies. However, ACTN3 polymorphism as a genetic marker for sport talent identification should be interpreted with great caution.
PMCID: PMC3592109  PMID: 23486986
α-actinin-3; genotype; power-orientated athletes
7.  AMPD1 rs17602729 is associated with physical performance of sprint and power in elite Lithuanian athletes 
BMC Genetics  2014;15:58.
The C34T genetic polymorphism (rs17602729) in the AMPD1 gene, encoding the skeletal muscle-specific isoform of adenosine monophosphate deaminase (AMPD1), is a common polymorphism among Caucasians that can impair exercise capacity. The aim of the present study was twofold: (1) to determine the C34T AMPD1 allele/genotype frequency distributions in Lithuanian athletes (n = 204, stratified into three groups: endurance, sprint/power and mixed) and compare them with the allele/genotype frequency distributions in randomly selected healthy Lithuanian non-athletes (n = 260) and (2) to compare common anthropometric measurements and physical performance phenotypes between the three groups of athletes depending on their AMPD1 genotype.
The results of our study indicate that the frequency of the AMPD1 TT genotype was 2.4% in the control group, while it was absent in the athlete group. There were significantly more sprint/power-orientated athletes with the CC genotype (86.3%) compared with the endurance-orientated athletes (72.9%), mixed athletes (67.1%), and controls (74.2%). We determined that the AMPD1 C34T polymorphism is not associated with aerobic muscle performance phenotype (VO2max). For CC genotype the short-term explosive muscle power value (based on Vertical Jump test) of athletes from the sprint/power group was significantly higher than that of the endurance group athletes (P < 0.05). The AMPD1 CC genotype is associated with anaerobic performance (Vertical Jump).
The AMPD1 C allele may help athletes to attain elite status in sprint/power-oriented sports, and the T allele is a factor unfavourable for athletics in sprint/power-oriented sports categories. Hence, the AMPD1 C allele can be regarded as a marker associated with the physical performance of sprint and power. Replications studies are required to confirm this association.
PMCID: PMC4032451  PMID: 24885427
Myoadenylate deaminase; Genetic polymorphism; Genotype; Sprint and power; Endurance
8.  Are ‘Endurance’ Alleles ‘Survival’ Alleles? Insights from the ACTN3 R577X Polymorphism 
PLoS ONE  2011;6(3):e17558.
Exercise phenotypes have played a key role for ensuring survival over human evolution. We speculated that some genetic variants that influence exercise phenotypes could be associated with exceptional survival (i.e. reaching ≥100years of age). Owing to its effects on muscle structure/function, a potential candidate is the Arg(R)577Ter(X) polymorphism (rs1815739) in ACTN3, the structural gene encoding the skeletal muscle protein α-actinin-3. We compared the ACTN3 R577X genotype/allele frequencies between the following groups of ethnically-matched (Spanish) individuals: centenarians (cases, n = 64; 57 female; age range: 100–108 years), young healthy controls (n = 283, 67 females, 216 males; 21±2 years), and humans who are at the two end-points of exercise capacity phenotypes, i.e. muscle endurance (50 male professional road cyclists) and muscle power (63 male jumpers/sprinters). Although there were no differences in genotype/allele frequencies between centenarians (RR:28.8%; RX:47.5%; XX:23.7%), and controls (RR:31.8%; RX:49.8%; XX:18.4%) or endurance athletes (RR:28.0%; RX:46%; XX:26.0%), we observed a significantly higher frequency of the X allele (P = 0.019) and XX genotype (P = 0.011) in centenarians compared with power athletes (RR:47.6%; RX:36.5%;XX:15.9%). Notably, the frequency of the null XX (α-actinin-3 deficient) genotype in centenarians was the highest ever reported in non-athletic Caucasian populations. In conclusion, despite there were no significant differences with the younger, control population, overall the ACTN3 genotype of centenarians resembles that of world-class elite endurance athletes and differs from that of elite power athletes. Our preliminary data would suggest a certain ‘survival’ advantage brought about by α-actinin-3 deficiency and the ‘endurance’/oxidative muscle phenotype that is commonly associated with this condition.
PMCID: PMC3048287  PMID: 21407828
9.  Elite athletes’ genetic predisposition for altered risk of complex metabolic traits 
BMC Genomics  2015;16(1):25.
Genetic variants may predispose humans to elevated risk of common metabolic morbidities such as obesity and Type 2 Diabetes (T2D). Some of these variants have also been shown to influence elite athletic performance and the response to exercise training. We compared the genotype distribution of five genetic Single Nucleotide Polymorphisms (SNPs) known to be associated with obesity and obesity co-morbidities (IGF2BP2 rs4402960, LPL rs320, LPL rs328, KCJN rs5219, and MTHFR rs1801133) between athletes (all male, n = 461; endurance athletes n = 254, sprint/power athletes n = 207), and controls (all male, n = 544) in Polish and Russian samples. We also examined the association between these SNPs and the athletes’ competition level (‘elite’ and ‘national’ level). Genotypes were analysed by Single-Base Extension and Real-Time PCR. Multinomial logistic regression analyses were conducted to assess the association between genotypes and athletic status/competition level.
IGF2BP2 rs4402960 and LPL rs320 were significantly associated with athletic status; sprint/power athletes were twice more likely to have the IGF2BP2 rs4402960 risk (T) allele compared to endurance athletes (OR = 2.11, 95% CI = 1.03-4.30, P <0.041), and non-athletic controls were significantly less likely to have the T allele compared to sprint/power athletes (OR = 0.62, 95% CI =0.43-0.89, P <0.0009). The control group was significantly more likely to have the LPL rs320 risk (G) allele compared to endurance athletes (OR = 1.26, 95% CI = 1.05-1.52, P <0.013). Hence, endurance athletes were the “protected” group being significantly (p < 0.05) less likely to have the risk allele compared to sprint/power athletes (IGF2BP2 rs4402960) and significantly (p < 0.05) less likely to have the risk allele compared to controls (LPL rs320). The other 3 SNPs did not show significant differences between the study groups.
Male endurance athletes are less likely to have the metabolic risk alleles of IGF2BP2 rs4402960 and LPL rs320, compared to sprint/power athletes and controls, respectively. These results suggest that some SNPs across the human genome have a dual effect and may predispose endurance athletes to reduced risk of developing metabolic morbidities, whereas sprint/power athletes might be predisposed to elevated risk.
PMCID: PMC4320608  PMID: 25612568
Genes; Exercise; Athletes; Obesity; Type 2 diabetes
10.  The FTO A/T Polymorphism and Elite Athletic Performance: A Study Involving Three Groups of European Athletes 
PLoS ONE  2013;8(4):e60570.
The FTO A/T polymorphism (rs9939609) is a strong candidate to influence obesity-related traits. Elite athletes from many different sporting disciplines are characterized by low body fat. Therefore, the aim of this study was to assess whether athletic status is associated with the FTO A/T polymorphism.
Subjects and Methods
A large cohort of European Caucasians from Poland, Russia and Spain were tested to examine the association between FTO A/T polymorphism (rs9939609) and athletic status. A total of 551 athletes were divided by type of sport (endurance athletes, n = 266 vs. sprint/power athletes, n = 285) as well as by level of competition (elite-level vs. national-level). The control group consisted of 1,416 ethnically-matched, non-athletic participants, all Europeans. Multinomial logistic regression analyses were conducted to assess the association between FTO A/T genotypes and athletic status/competition level.
There were no significantly greater/lesser odds of harbouring any type of genotype when comparing across athletic status (endurance athletes, sprint/power athletes or control participants). These effects were observed after controlling for sex and nationality. Furthermore, no significantly greater/lesser odds ratios were observed for any of the genotypes in respect to the level of competition (elite-level vs. national-level).
The FTO A/T polymorphism is not associated with elite athletic status in the largest group of elite athletes studied to date. Large collaborations and data sharing between researchers, as presented here, are strongly recommended to enhance the research in the field of exercise genomics.
PMCID: PMC3616005  PMID: 23573268
Biology of Sport  2014;31(2):105-108.
α-Actinin-3 (ACTN3) has been proposed to regulate skeletal muscle differentiation and hypertrophy through its interaction with the signalling protein calcineurin. Since the inhibition of calcineurin potentiates the production of testosterone, we hypothesized that α-actinin-3 deficiency (predicted from the ACTN3 XX genotype) may influence serum levels of testosterone of athletes. Objective: To investigate the association of ACTN3 gene R577X polymorphism with resting testosterone levels in athletes. Methods: A total of 209 elite Russian athletes from different sports (119 males, 90 females) were genotyped for ACTN3 gene R577X polymorphism by real-time PCR. Resting testosterone was examined in serum of athletes using enzyme immunoassay. Results: The mean testosterone levels were significantly higher in both males and females with the ACTN3 R allele than in XX homozygotes (males: RR: 24.9 (5.7), RX: 21.8 (5.5), XX: 18.6 (4.9) ng · mL-1, P = 0.0071; females: RR: 1.43 (0.6), RX: 1.21 (0.71), XX: 0.79 (0.66) ng · mL-1, P = 0.0167). Conclusions: We found that the ACTN3 R allele was associated with high levels of testosterone in athletes, and this may explain, in part, the association between the ACTN3 RR genotype, skeletal muscle hypertrophy and power athlete status.
PMCID: PMC4042656  PMID: 24899773
ACTN3; gene polymorphism; testosterone; calcineurin; muscle hypertrophy
12.  EPAS1 gene variants are associated with sprint/power athletic performance in two cohorts of European athletes 
BMC Genomics  2014;15(1):382.
The endothelial PAS domain protein 1 (EPAS1) activates genes that are involved in erythropoiesis and angiogenesis, thus favoring a better delivery of oxygen to the tissues and is a plausible candidate to influence athletic performance. Using innovative statistical methods we compared genotype distributions and interactions of EPAS1 SNPs rs1867785, rs11689011, rs895436, rs4035887 and rs1867782 between sprint/power athletes (n = 338), endurance athletes (n = 254), and controls (603) in Polish and Russian samples. We also examined the association between these SNPs and the athletes’ competition level (‘elite’ and ‘sub-elite’ level). Genotyping was performed by either Real-Time PCR or by Single-Base Extension (SBE) method.
In the pooled cohort of Polish and Russian athletes, 1) rs1867785 was associated with sprint/power athletic status; the AA genotype in rs1867785 was underrepresented in the sprint/power athletes, 2) rs11689011 was also associated with sprint/power athletic status; the TT genotype in rs11689011 was underrepresented sprint/power athletes, and 3) the interaction between rs1867785, rs11689011, and rs4035887 was associated with sprint/power athletic performance; the combinations of the AA genotype in rs4035887 with either the AG or GG genotypes in rs1867785, or with the CT or CC genotypes in rs11689011, were underrepresented in two cohorts of sprint/power athletes.
Based on the unique statistical model rs1867785/rs11689011 are strong predictors of sprint/power athletic status, and the interaction between rs1867785, rs11689011, and rs4035887 might contribute to success in sprint/power athletic performance.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-382) contains supplementary material, which is available to authorized users.
PMCID: PMC4035083  PMID: 24884370
Athletic performance; EPAS1; Genomics; Genes; Endurance; Sprint
Biology of Sport  2014;31(1):21-25.
The GNB3 gene encodes the beta 3 subunit of heterotrimeric G-proteins that are key components of intracellular signal transduction between G protein-coupled receptors (GPCR) and intracellular effectors and might be considered as a potential candidate gene for physical performance.
The aim of this study was to compare frequency distribution of the common C to T polymorphism at position 825 (C825T) of the GNB3 gene between athletes and nonathletic controls of the Polish population as well as to compare the genotype distribution and allele frequency of C825T variants within a group of athletes, i.e. between athletes of sports of different metabolic demands and competitive levels.
The study was performed in a group of 223 Polish athletes of the highest nationally competitive standard (123 endurance-oriented athletes and 100 strength/ power athletes). Control samples were prepared from 354 unrelated, sedentary volunteers.
The χ2 test revealed no statistical differences between the endurance-oriented athletes and the control group or between sprint/strength athletes and the control group across the GNB3 825C/T genotypes. There were no male-female genotype or allele frequency differences in controls or in either strength/power or endurance-oriented athletes. No statistically significant differences in either allele frequencies or genotype distribution were noted between the top-elite, elite or sub-elite of endurance-oriented and strength/power athletes and the control group.
No association between elite status of Polish athletes and the GNB3 C825T polymorphic site has been found.
PMCID: PMC3994581  PMID: 24917685
GNB3 C825T; gene polymorphism; performance; elite athletes status
14.  Effects of Low-Volume High-Intensity Interval Training (HIT) on Fitness in Adults: A Meta-Analysis of Controlled and Non-Controlled Trials 
Sports Medicine (Auckland, N.z.)  2014;44(7):1005-1017.
Low-volume high-intensity interval training (HIT) appears to be an efficient and practical way to develop physical fitness.
Our objective was to estimate meta-analysed mean effects of HIT on aerobic power (maximum oxygen consumption [VO2max] in an incremental test) and sprint fitness (peak and mean power in a 30-s Wingate test).
Data Sources
Five databases (PubMed, MEDLINE, Scopus, BIOSIS and Web of Science) were searched for original research articles published up to January 2014. Search terms included ‘high intensity’, ‘HIT’, ‘sprint’, ‘fitness’ and ‘VO2max’.
Study Selection
Inclusion criteria were fitness assessed pre- and post-training; training period ≥2 weeks; repetition duration 30–60 s; work/rest ratio <1.0; exercise intensity described as maximal or near maximal; adult subjects aged >18 years.
Data Extraction
The final data set consisted of 55 estimates from 32 trials for VO2max, 23 estimates from 16 trials for peak sprint power, and 19 estimates from 12 trials for mean sprint power. Effects on fitness were analysed as percentages via log transformation. Standard errors calculated from exact p values (where reported) or imputed from errors of measurement provided appropriate weightings. Fixed effects in the meta-regression model included type of study (controlled, uncontrolled), subject characteristics (sex, training status, baseline fitness) and training parameters (number of training sessions, repetition duration, work/rest ratio). Probabilistic magnitude-based inferences for meta-analysed effects were based on standardized thresholds for small, moderate and large changes (0.2, 0.6 and 1.2, respectively) derived from between-subject standard deviations (SDs) for baseline fitness.
A mean low-volume HIT protocol (13 training sessions, 0.16 work/rest ratio) in a controlled trial produced a likely moderate improvement in the VO2max of active non-athletic males (6.2 %; 90 % confidence limits ±3.1 %), when compared with control. There were possibly moderate improvements in the VO2max of sedentary males (10.0 %; ±5.1 %) and active non-athletic females (3.6 %; ±4.3 %) and a likely small increase for sedentary females (7.3 %; ±4.8 %). The effect on the VO2max of athletic males was unclear (2.7 %; ±4.6 %). A possibly moderate additional increase was likely for subjects with a 10 mL·kg−1·min−1 lower baseline VO2max (3.8 %; ±2.5 %), whereas the modifying effects of sex and difference in exercise dose were unclear. The comparison of HIT with traditional endurance training was unclear (−1.6 %; ±4.3 %). Unexplained variation between studies was 2.0 % (SD). Meta-analysed effects of HIT on Wingate peak and mean power were unclear.
Low-volume HIT produces moderate improvements in the aerobic power of active non-athletic and sedentary subjects. More studies are needed to resolve the unclear modifying effects of sex and HIT dose on aerobic power and the unclear effects on sprint fitness.
PMCID: PMC4072920  PMID: 24743927
15.  Genetic influence on athletic performance 
Current opinion in pediatrics  2013;25(6):653-658.
Purpose of review
The purpose of this review is to summarize the existing literature on the genetics of athletic performance, with particular consideration for the relevance to young athletes.
Recent findings
Two gene variants, ACE I/D and ACTN3 R577X, have been consistently associated with endurance (ACE I/I) and power-related (ACTN3 R/R) performance, though neither can be considered predictive. The role of genetic variation in injury risk and outcomes is more sparsely studied, but genetic testing for injury susceptibility could be beneficial in protecting young athletes from serious injury. Little information on the association of genetic variation with athletic performance in young athletes is available; however, genetic testing is becoming more popular as a means of talent identification. Despite this increase in the use of such testing, evidence is lacking for the usefulness of genetic testing over traditional talent selection techniques in predicting athletic ability, and careful consideration should be given to the ethical issues surrounding such testing in children.
A favorable genetic profile, when combined with an optimal training environment, is important for elite athletic performance; however, few genes are consistently associated with elite athletic performance, and none are linked strongly enough to warrant their use in predicting athletic success.
PMCID: PMC3993978  PMID: 24240283
Genomics; endurance; fitness; sport
16.  The ACTN3 R577X nonsense allele is under-represented in elite-level strength athletes 
Previous reports have shown a lower proportion of the ACTN3 X/X genotype (R577X nonsense polymorphism) in sprint-related athletes compared to the general population, possibly attributed to impairment of muscle function related to α-actinin-3 deficiency. In the present study, we examined the frequency of the X/X genotype in both Black and White elite-level bodybuilders and strength athletes in comparison to the general population. A reference population of 668 Whites (363 men and 305 women) and 208 Blacks (98 men and 110 women) was genotyped for the ACTN3 R577X polymorphism. Strength athletes (52 white and 23 black; 4 women) consisting predominantly of world class and locally competitive bodybuilders, and elite powerlifters were recruited and similarly genotyped. Significantly lower X/X genotype frequencies were observed in the athletes (6.7%) vs controls (16.3%; P = 0.005). The X/X genotype was significantly lower in White athletes (9.7%) vs controls (19.9%; P = 0.018). No black athletes (0%) were observed with the X/X genotype, though this finding only approached statistical significance vs controls (4.8%; P = 0.10). The results indicate that the ACTN3 R577X nonsense allele (X) is under-represented in elite strength athletes, consistent with previous reports indicating that α-actinin-3 deficiency appears to impair muscle performance.
PMCID: PMC2668151  PMID: 18043716
skeletal muscle; polymorphism; muscle strength
17.  ACTN3 R577X Genotypes Associate with Class II and Deep Bite Malocclusions 
α-actinins are myofibril anchor proteins which influence contractile properties of skeletal muscle. ACTN2 is expressed in slow type I and fast type II fibers whereas ACTN3 is expressed only in fast fibers. ACTN3 homozygosity for the 577X stop codon (i.e. changing 577RR to 577XX - the R577X polymorphism) results in the absence of α-actinin-3 in about 18% of Europeans, diminished fast contractile ability, enhanced endurance performance and reduced bone mass or bone mineral density. We have examined ACTN3 expression and genetic variation in masseter muscle of orthognathic surgery patients to determine genotype associations with malocclusion.
Clinical information, masseter muscle biopsies and saliva samples were obtained from 60 subjects. Genotyping for ACTN3 SNPs, RT-PCR quantitation of muscle gene message and muscle morphometric fiber type properties were compared to determine statistical differences between genotype and phenotype.
Muscle mRNA expression level was significantly different for ACTN3 SNP genotypes (p<0.01). The frequency of ACTN3 genotypes was significantly different for sagittal and vertical classifications of malocclusion with the clearest association being elevated 577XX genotype in skeletal class II malocclusion (p = 0.003). This genotype also resulted in significantly smaller diameter of fast type II fibers in masseter muscle (p = 0.002).
ACTN3 577XX is overrepresented in skeletal class II malocclusion, suggesting a biologic influence during bone growth. ACTN3 577XX is underrepresented in deep bite malocclusion, suggesting muscle differences contribute to variations in vertical facial dimensions.
PMCID: PMC4254725  PMID: 25439211
18.  ACTN3 R577X Polymorphism and Neuromuscular Response to Resistance Training 
The R577X polymorphism at the ACTN3 gene has been associated with muscle strength, hypertrophy and athletic status. The X allele, which is associated with the absence of ACTN3 protein is supposed to impair performance of high force/velocity muscle contractions. The purpose of the present study was to investigate the association of the R577X polymorphism with the muscle response to resistance training in young men. One hundred forty one men performed two resistance training sessions per week for 11 weeks. Participants were tested for 1RM bench press, knee extensors peak torque, and knee extensors muscle thickness at baseline and after the training period. Genotyping was conducted using de DdeI restriction enzyme. Genotype distribution was 34.4% for RR, 47% for RX and 18.6% for the XX genotype. According to the results, the R577X polymorphism at the ACTN3 gene is not associated with baseline muscle strength or with the muscle strength response to resistance training. However, only carriers of the R allele showed increases in muscle thickness in response to training.
Key pointsACTN3 Genotype distribution in the present study was similar to others populations (34.4% for RR, 47% for RX, and 18.6% for the XX).The R577X polymorphism at the ACTN3 gene is not associated with baseline muscle strength or with the muscle strength response to resistance training.It appears that the R allele carriers respond better to muscle thickness gains in response to training.
PMCID: PMC3761844  PMID: 24149888
Muscle strength; muscle hypertrophy; peak torque; genotype; alpha-actinin 3; knee extensor
19.  Variable number of tandem repeat polymorphisms of the interleukin-1 receptor antagonist gene IL-1RN: a novel association with the athlete status 
BMC Medical Genetics  2010;11:29.
The interleukin-1 (IL-1) family of cytokines is involved in the inflammatory and repair reactions of skeletal muscle during and after exercise. Specifically, plasma levels of the IL-1 receptor antagonist (IL-1ra) increase dramatically after intense exercise, and accumulating evidence points to an effect of genetic polymorphisms on athletic phenotypes. Therefore, the IL-1 family cytokine genes are plausible candidate genes for athleticism. We explored whether IL-1 polymorphisms are associated with athlete status in European subjects.
Genomic DNA was obtained from 205 (53 professional and 152 competitive non-professional) Italian athletes and 458 non-athlete controls. Two diallelic polymorphisms in the IL-1β gene (IL-1B) at -511 and +3954 positions, and a variable number tandem repeats (VNTR) in intron 2 of the IL-1ra gene (IL-1RN) were assessed.
We found a 2-fold higher frequency of the IL-1RN 1/2 genotype in athletes compared to non-athlete controls (OR = 1.93, 95% CI = 1.37-2.74, 41.0% vs. 26.4%), and a lower frequency of the 1/1 genotype (OR = 0.55, 95% CI = 0.40-0.77, 43.9% vs. 58.5%). Frequency of the IL-1RN 2/2 genotype did not differ between groups. No significant differences between athletes and controls were found for either -511 or +3954 IL-1B polymorphisms. However, the haplotype (-511)C-(+3954)T-(VNTR)2 was 3-fold more frequent in athletes than in non-athletes (OR = 3.02, 95% CI = 1.16-7.87). Interestingly, the IL-1RN 1/2 genotype was more frequent in professional than in non-professional athletes (OR = 1.92, 95% CI = 1.02-3.61, 52.8% vs. 36.8%).
Our study found that variants at the IL-1ra gene associate with athletic status. This confirms the crucial role that cytokine IL-1ra plays in human physical exercise. The VNTR IL-1RN polymorphism may have implications for muscle health, performance, and/or recovery capacities. Further studies are needed to assess these specific issues. As VNTR IL-1RN polymorphism is implicated in several disease conditions, athlete status may constitute a confounding variable that will need to be accounted for when examining associations of this polymorphism with disease risk.
PMCID: PMC2837019  PMID: 20175886
20.  The ACTN3 R577X variant in sprint and strength performance 
The aim of this study is to examine the association between the distribution of ACTN3 genotypes and alleles in power, speed, and strength-oriented athletics.
ACTN3 genotyping was carried out for a total of 975 Korean participants: top-level sprinters (n = 58), top-level strength athletes (n = 63), and healthy controls (n = 854).
Genetic associations were evaluated by chi-squire test or Fisher’s exact test. In the power-oriented group composed of sprinters and strength athletes, the frequency of the XX genotype was significantly underrepresented (11.6%) in comparison to its representation in the control group (11.6% versus 19.1%, P < 0.05). When the power-oriented group was divided into strength-oriented and speed-oriented groups, no significant difference in the ACTN3 XX genotype was found between the strength-oriented athletes and the controls (15.9% versus 19.1%, P < 0.262). Only the speed-oriented athletes showed significant differences in the frequency distributions of the ACTN3 XX genotype (6.9% versus 19.1%, P < 0.05) from that of the controls.
The ACTN3 genotype seems to mainly affect sports performance and especially speed.
PMCID: PMC4322025  PMID: 25671201
α-actinin-3; human performance; population genetics; fast-twitch muscle fibers; contractile property
21.  ACTN3 R577X polymorphism and long-term survival in patients with chronic heart failure 
Previous studies have shown the occurrence of actinin-3 deficiency in the presence of the R577X polymorphism in the ACTN3 gene. Our hypothesis is that this deficiency, by interfering with the function of skeletal muscle fiber, can result in a worse prognosis in patients with chronic heart failure.
A prospective cohort study was conducted from 2002 to 2004. The eligibility criteria included diagnosis of chronic heart failure stage C from different etiologies. We excluded all patients with concomitant disease that could be related to poor prognosis. ACTN3 rs1815739 (R577X) polymorphism was detected by high resolution melting analysis. Survival curves were calculated with the Kaplan-Meier method and evaluated with the log-rank statistic. The relationship between the baseline variables and the composite end-point of all-cause death was assessed using a Cox proportional hazards survival model.
A total of 463 patients were included in this study. The frequency of the ACTN3 577X variant allele was 39.0%. The LVEF mean was 45.6 ± 18.7% and the most common etiology of this study was hypertensive. After a follow-up of five years, 239 (51.6%) patients met the pre-defined endpoint. Survival curves showed higher mortality in patients carrying RX or XX genotypes compared with patients carrying RR genotype (p = 0.01).
R577X polymorphism in the ACTN3 gene was independently associated with worse survival in patients with chronic heart failure. Further studies are necessary to ensure its use as a marker of prognosis for this syndrome.
PMCID: PMC4113663  PMID: 25059829
ACTN3; R577X; Polymorphism; Heart failure
22.  The influence of ACE ID and ACTN3 R577X polymorphisms on lower-extremity function in older women in response to high-speed power training 
BMC Geriatrics  2013;13:131.
We studied the influence of the ACE I/D and ACTN3 R577X polymorphisms (single or combined) on lower-extremity function in older women in response to high-speed power training.
One hundred and thirty-nine healthy older Caucasian women participated in this study (age: 65.5 ± 8.2 years, body mass: 67.0 ± 10.0 kg and height: 1.57 ± 0.06 m). Walking speed (S10) performance and functional capacity assessed by the “get-up and go” (GUG) mobility test were measured at baseline (T1) and after a consecutive 12-week period of high-speed power training (40-75% of one repetition maximum in arm and leg extensor exercises; 3 sets 4–12 reps, and two power exercises for upper and lower extremity). Genomic DNA was extracted from blood samples, and genotyping analyses were performed by PCR methods. Genotype distributions between groups were compared by Chi-Square test and the gains in physical performance were analyzed by two-way, repeated-measures ANOVA.
There were no significant differences between genotype groups in men or women for adjusted baseline phenotypes (P > 0.05). ACE I/D and ACTN3 polymorphisms showed a significant interaction genotype-training only in S10 (P = 0.012 and P = 0.044, respectively) and not in the GUG test (P = 0.311 and P = 0.477, respectively). Analyses of the combined effects between genotypes showed no other significant differences in all phenotypes (P < 0.05) at baseline. However, in response to high-speed power training, a significant interaction on walking speed (P = 0.048) was observed between the “power” (ACTN3 RR + RX & ACE DD) versus “non-power” muscularity-oriented genotypes (ACTN3 XX & ACE II + ID)].
Thus, ACE I/D and ACTN3 R577X polymorphisms are likely candidates in the modulation of exercise-related gait speed phenotype in older women but not a significant influence in mobility traits.
PMCID: PMC4029788  PMID: 24313907
Resistance training; Angiotensin converting-enzyme; Alpha-Actinin-3; Women; Lower mobility
23.  Should Athletes Return to Activity After Cryotherapy? 
Journal of Athletic Training  2014;49(1):95-96.
Bleakley CM, Costello JT, Glasgow PD. Should athletes return to sport after applying ice? A systematic review of the effect of local cooling on functional performance. Sports Med. 2012; 42(1):69–87.
Clinical Question
Does local tissue cooling affect immediate functional performance outcomes in a sport situation?
Data Sources
Studies were identified by searching MEDLINE, the Cochrane Central Register of Controlled Trials, and EMBASE, each from the earliest available record through April 2011. Combinations of 18 medical subheadings or key words were used to complete the search.
Study Selection
This systematic review included only randomized controlled trials and crossover studies published in English that examined human participants who were treated with a local cooling intervention. At least 1 functional performance outcome that was measured before and after a cooling intervention had to be reported. Excluded were studies using whole-body cryotherapy or cold-water immersion above the waist and studies that measured strength or force production during evoked muscle contraction.
Data Extraction
Data were extracted by 2 authors using a customized form to evaluate relevant data on study design, eligibility criteria, detailed characteristics of cooling protocols, comparisons, and outcome measures. Disagreement was resolved by consensus or third-party adjudication. To perform an intent-to-treat analysis when possible, data were extracted according to the original allocation groups, and losses to follow-up were noted. The review authors were not blinded to the study author, institution, or journal. For each study, mean differences or standardized mean differences and 95% confidence intervals were calculated for continuous outcomes using RevMan (version 5.1; The Nordic Cochrane Centre, Copenhagen, Denmark). Treatment effects were based on between-groups comparisons (cryotherapy versus control) using postintervention outcomes or within-group comparisons (precryotherapy versus postcryotherapy). If continuous data were missing standard deviations, other statistics including confidence intervals, standard error, t values, P values, or F values were used to calculate the standard deviation. The Cochrane risk-of-bias tool was used to assess the methodologic quality of included studies. Each study was evaluated for sequence generation, allocation concealment, assessor blinding, and incomplete outcome data. Studies were graded as low or high based on the criteria met, but the risk of bias across the studies was consistently high, so meaningful subgroup classifications were not possible. Differences in study quality and intervention details, including duration of cryotherapy interventions and time periods after intervention before follow-up, were potential sources of bias and considered for a subgroup analysis.
Main Results
Using the search criteria, the authors originally identified 1449 studies. Of these, after title and abstract review, 99 studies were deemed potentially relevant and kept for further analysis (1350 studies were excluded). Of the 99 potentially relevant studies, 35 were included in the final review (64 studies were excluded), with relevant outcomes of strength, power, vertical jump, endurance, agility, speed, performance accuracy, and dexterity reported. The 64 excluded studies were rejected due to intervention relevancy, outcome relevancy, and non-English language. In the 35 studies meeting the inclusion criteria, 665 healthy participants were assessed. Muscle strength (using an isokinetic dynamometer, cable tensiometer, strain-gauge device, or load cell) was assessed in 25 studies, whole-body exercise (vertical jump height, power, timed hop test, sprint time, and time taken to complete running-based agility tests, including carioca runs, shuttle sprints, T-shuttle, and cocontraction tests) was assessed in 6, performance accuracy (throwing or shooting) was assessed in 2, and hand dexterity was assessed in 2. Outcomes before and immediately after cryotherapy intervention were reported in all studies; additional outcome assessments at times ranging from 5 to 180 minutes postintervention were recorded in 11 studies. The review authors reported a high risk of bias: selection bias (poor randomization and concealment of group allocation), performance and detection bias (poor blinding of assessors), and attrition bias (incomplete data). Because of the diversity of studies, particularly with respect to cryotherapy protocols and the potential for rewarming before the posttest, the effects of cryotherapy on functional performance were mixed. From the included studies, the authors concluded that cryotherapy treatment reduced upper and lower extremity muscle strength immediately after cryotherapy. However, increases in force output after cryotherapy were reported in 5 studies. Regardless of the effect of cryotherapy on strength, the clinical meaningfulness of most of the data may not be important due to variability and small effects. Studies reporting outcomes of muscle endurance resulted in conflicting evidence: endurance increased immediately after cryotherapy in 6, whereas muscle endurance decreased in 3 . These conflicting results limit the ability to draw clinically relevant conclusions about the effect of cryotherapy on muscle endurance. The majority of studies evaluating whole-body exercise demonstrated decreases in performance after cryotherapy; these outcomes included vertical jump, sprint, and agility, even when cryotherapy was applied only to a body part. Additionally, cryotherapy appeared to decrease hand dexterity and throwing accuracy immediately after intervention, although an increase in shooting performance postintervention was reported in 1 study .
The authors suggested that the available evidence indicates that athletic performance may be adversely affected when athletes return to play immediately after cryotherapy treatments. Many of the included studies used variable cooling protocols, reflecting differences in time, temperature, and mode of cryotherapy. The majority of the included studies used cryotherapy for at least 20 minutes. However, when considering an immediate return to activity, this cooling duration may not be clinically relevant because cryotherapy applications during practice and competitions usually last less than 20 minutes. When immediate return to activity occurs after cryotherapy, short-duration cold applications or progressive warm-ups should be implemented to prevent a deleterious effect on functional performance.
PMCID: PMC3917303  PMID: 23724775
cold modalities; functional performance; strength; endurance
24.  ACTN3 genotype influences muscle performance through the regulation of calcineurin signaling  
The Journal of Clinical Investigation  2013;123(10):4255-4263.
α-Actinin-3 deficiency occurs in approximately 16% of the global population due to homozygosity for a common nonsense polymorphism in the ACTN3 gene. Loss of α-actinin-3 is associated with reduced power and enhanced endurance capacity in elite athletes and nonathletes due to “slowing” of the metabolic and physiological properties of fast fibers. Here, we have shown that α-actinin-3 deficiency results in increased calcineurin activity in mouse and human skeletal muscle and enhanced adaptive response to endurance training. α-Actinin-2, which is differentially expressed in α-actinin-3–deficient muscle, has higher binding affinity for calsarcin-2, a key inhibitor of calcineurin activation. We have further demonstrated that α-actinin-2 competes with calcineurin for binding to calsarcin-2, resulting in enhanced calcineurin signaling and reprogramming of the metabolic phenotype of fast muscle fibers. Our data provide a mechanistic explanation for the effects of the ACTN3 genotype on skeletal muscle performance in elite athletes and on adaptation to changing physical demands in the general population. In addition, we have demonstrated that the sarcomeric α-actinins play a role in the regulation of calcineurin signaling.
PMCID: PMC3784532  PMID: 24091322
25.  Association of the ACTN3 Genotype and Physical Functioning With Age in Older Adults 
The purpose of this study was to examine the association of the alpha-actinin-3 (ACTN3) R577X polymorphism on muscle function and physical performance in older adults.
We measured knee extensor torque, midthigh muscle cross-sectional area, muscle quality, short physical performance battery score, and 400-meter walk time at baseline and after 5 years in white older adults aged 70–79 years in the Health, Aging and Body Composition Study cohort (n = 1367). Incident persistent lower extremity limitation (PLL) over 5 years was additionally assessed. We also examined white men in the Osteoporotic Fractures in Men Study, a longitudinal, observational cohort (n = 1152) of men 65 years old or older as a validation cohort for certain phenotypes.
There were no significant differences between genotype groups in men or women for adjusted baseline phenotypes. Male X-homozygotes had a significantly greater adjusted 5-year increase in their 400-meter walk time compared to R-homozygotes and heterozygotes (p = .03). In women, X-homozygotes had a ~35% greater risk of incident PLL compared to R-homozygotes (hazard ratio = 0.65, 95% confidence interval = 0.44–0.94). There were no other significant associations between any of the phenotypes and ACTN3 genotype with aging in either cohort.
The ACTN3 polymorphism may influence declines in certain measures of physical performance with aging in older white adults, based on longitudinal assessments. However, the influence of the ACTN3 R577X polymorphism does not appear to have a strong effect on skeletal muscle–related phenotypes based on the strength and consistency of the associations and lack of replication with regard to specific phenotypes.
PMCID: PMC2728123  PMID: 19038838
Genetics; Elderly; Sarcopenia; Skeletal muscle

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