Association Of Single Nucleotide Polymorphisms Of Actn3 With Sport Ability And Acute Ankle Sprains

Introduction: The alpha-actinins are a family of actin-binding proteins. Two calcium-insensitiveα-actinins isoforms (ACTN2 and ACTN3) are expressed in skeletal muscle. They constitute the major structural components of the sarcomeric Z-line involved in anchoring together the actin-containing thin filaments. In humans, ACTN2 is found in skeletal and cardiac muscle fibers, while the expression ofα-actinin-3 is restricted to a subset of fast glycolytic skeletal muscle typeⅡx fibres. Moreover,α-actinin-2 andα-actinin-3 also interact with many muscle proteins carry out a variety of signaling and metabolic functions.The R577X SNP originated as a result of a C-to-T transition at position 1747 in exon 16 that replaces an arginine codon 577(577R) for a premature stop codon (577X). The X-allele fail to produceα-actinin-3 protein, but without association with any disease phenotype. A previous study has suggested that no other mammal has polymorphism for null alleles of ACTN3 except human. This allele is found in every human population tested. There are approximate 19% of Caucasian (combined male and female) who are ACTN3 deficient, and the X-allele frequency is greater than 15% in several of the world's general populations. Theα-actinin has been shown to be highly conserved, and recent evidence has proposed that absence of ACTN3 gene function shows positive selection in humans owing to its effect on muscle metabolism. Recently, there are more and more studies indicating that the ACTN3 genotype impact on human exercise performance phenotypes. The research of the R577X polymorphism in elite Caucasian athletes demonstrated RR homozygotes are over-represented in male and female elite sprint and power athletes relative to those in controls. The XX genotype was significantly associated with female elite endurance athletic performance, without the same effect on male endurance athletes. Similar findings have been replicated to have confirmed these associations and a number of cross-sectional studies have also supported that there is a positive association between the R-allele and high velocity muscle contractions. Furthermore, recent study has shown that the proportions of type IIx (fast-twitch glycolytic) fibers was greater in the RR than those in the XX genotype group, and ACTN3 protein content is higher in type IIx compared with type IIa fibers.Ankle sprains are one of the more common sites of musculoskeletal injuries during physical activity. Several extrinsic and intrinsic factors have been shown to be associated with these injuries. Recent reviews indicate that a genetic component has been implicated in those tendons and ligaments injuries. Sequence variants within genes that encode for several tendon and/or ligament extracellular matrix proteins have been shown to be associated with specific musculoskeletal soft tissues injuries. Polymorphisms within the TNC, COL5A1 and MMP3 genes have been associated with chronic Achilles tendinopathy in a physically active population. The variant within the TNC gene also appears to co-segregate with Achilles tendon ruptures, while sequence variants within the COL1A1, COL12A1 and COL5A1 genes have been shown to be associated with cruciate ligament ruptures and/or shoulder dislocations. However, the exact mechanisms which cause these acute ankle injuries are unknown. Muscle weakness/imbalance has been shown to be associated with ankle sprains, and therefore increased muscle strength/power may improve ankle sprains. The ACTN3 gene, which is only expressed in the Z line of fast glycolytic muscle fiber was found to associate with power/strength performance.In Caucasian, the associations of ACTN3 R577X with athletic performance have been clearly observed in elite-level athletes, but studies involving non-athletes have provided many confounded results (Moran et al., 2007; Santiago et al., 2009). The functional relationships between ACTN3 R577X polymorphism and physical functioning of skeletal muscle in Chinese non-athletes have not been examined. Under the hypothesis that the influence of the ACTN3 R577X polymorphism on athletic performance in Chinese is in accordance with the influence in Caucasian, it would be predicted that the ACTN3 homozygotes (RR) would have higher baseline muscle power/strength compared with the homozygotes (XX). We also hypothesized that the XX genotype would have more endurance compared with the homozygotes (RR). To test this hypothesis, and determine the association of the ACTN3 R577X polymorphism with physical- and performance-related phenotypes in a Chinese non-athlete population, we executed an association analysis using 452 Chinese young male soldiers for body composition-, strength/power- and endurance-related traits.In Caucasian, the associations of ACTN3 R577X with endurance performance have been clearly observed in elite-level athletes, but studies involving Chinese athletes have not been examined. We hypothesized that the frequency of ACTN3 XX genotype is higher and that of RR is lower among Han Chinese athletes. To test this hypothesis, we sought to determine the association of the ACTN3 R577X polymorphism with endurance athletes in China.At present, the associations of ACTN3 with muscle strength/power performance have been clearly observed in many studies. To the best of our knowledge, however, no information is available concerning the association between ACTN3 gene polymorphisms and acute ankle sprains. Therefore, the principal aim of this study was to determine the genetic association between the ACTN3 gene and acute ankle sprains in a young Chinese Han population.Objective:Previous studies have shown highly significant association between ACTN3 genotype and sprint/power performance, while the nonfunctional allele (577X) was believed to provide an advantage for endurance performance. First, we examined the distribution of ACTN3 genotypes and alleles and analyzed the association between ACTN3 genotypes and athletic performance in Chinese young male soldiers. Second, in this study we tested whether XX genotype was over-represented in Chinese endurance athletes compared to the general population.Third, the aim of this study was also to investigate if the ACTN3 gene polymorphism is associated with acute ankle sprains in Chinese young soldiers.Methods:In a study of 452 Chinese young male soldiers, we examined the distribution of ACTN3 genotypes and alleles and analyzed the association between ACTN3 genotypes and athletic performance.In a study of 250 Chinese endurance athletes of provincial or national competitive standard and 450 controls, we examined the distribution of ACTN3 genotypes and alleles and analyzed the association between ACTN3 genotypes and athletic performance.One hundred and forty-two participants with clinically and surgically diagnosed acute ankle sprains(AAS), as well as 280 physically active controls participants (CON) without any history of ankle sprains were included in this case-control genetic association study.The ACTN3 allelic variant and genotype was analyzed by Q-PCR.Results:1. The frequencies of the ACTN3 R577X genotype (RR 39.8%, RX 43.4%, and XX 16.8%) and R577X allele (R 61.5%, X 38.5%) were significantly consistent with the frequencies of Caucasian. We only observed a significant association between ACTN3 R577X genotypes and grip strength. Subjects with the XX genotype displayed significantly lower handgrip strength compared with individuals with RR (P = 0.007) genotypes, but the difference between XX and RX means (P = 0.121) and that between RR and RX means (P = 0.117) was not significant. We did not observe a predominant association between the ACTN3 R577X genotypes and sprint phenotypes and endurance phenotypes.2. We proved that the ACTN3 XX genotype (21.2 vs. 15.8%; P = 0.02) and X allele (51.3 vs. 41.1%; P = 0.019) were significantly over-represented in female endurance athletes compared to controls, while no genotype-related differences were observed in male endurance athletes. Besides, the frequency of the ACTN3 XX genotype (28.6%) was the highest in a group of highly elite athletes compared with other groups, which supported the hypothesis that the absence ofα-actinin-3 provided some sort of advantage for endurance athletes.3. The distribution of the ACTN3 gene in the AAS and controls showed significant differences with both the frequencies of the ACTN3 RR genotype (23.2 vs. 35%; P = 0.011) and R allele (47.9 vs. 58.9%; P = 0.002). The RR genotype of the ACTN3 was significantly low-represented in the AAS group compared with the controls (23.2% vs 35%; odds ratio = 1.8; 95% confidence interval, 1.1-2.8; P = 0.014). Compared with healthy controls, there was a decreasing linear trend (P = 0.01) in the 577RR genotype with increasing AAS grade.Conclusions:①Our results indicate that ACTN3 R577X polymorphism is only associated with grip strength in Chinese young male soldiers.②Our results indicated that ACTN3 R577X polymorphism was associated with endurance performance in female athletes but not male athletes in China.③The ACTN3 R577X is associated with AAS in Chinese participants in this study. This is the first study to suggest that individual with a RR genotype are at decreased risk of AAS. Further studies are required to explore and replicate these findings.