Alison V. September

The Guanine-Thymine Dinucleotide Repeat Polymorphism Within the Tenascin-C Gene Is Associated With Achilles Tendon Injuries

Background Although there is a high incidence of tendon injury as a result of participation in physical activity, the mechanisms responsible for such injuries are poorly understood. Investigators have suggested that some people may have a genetic predisposition to develop tendon injuries; in particular, genes on the tip of the long arm of chromosome 9 might, at least in part, be associated with this condition. The tenascin-C gene, which has been mapped to chromosome 9q32-q34, encodes for a structural component of tendons. Hypothesis The tenascin-C gene is associated with Achilles tendon injury. Study Design Case control study; Level of evidence, 3. Methods A total of 114 physically active white subjects with symptoms of Achilles tendon injury and 127 asymptomatic, physically active white control subjects were genotyped for the guanine-thymine dinucleotide repeat polymorphism within the tenascin-C gene. Results A significant difference in the allele frequencies of this polymorphism existed between the 2 groups of subjects (χ2 = 51.0, P =. 001). The frequencies of the alleles containing 12 repeats (symptomatic group, 18.9% vs control group, 10.2%) and 14 repeats (symptomatic group, 9.2% vs control group, 0.8%) were significantly higher in the symptomatic group, while the frequencies of the alleles containing 13 repeats (symptomatic group, 8.8% vs control group, 24.0%) and 17 repeats (symptomatic group, 7.5% vs control group, 20.1%) were significantly lower in this same group. Subjects who were homozygous or heterozygous for the underrepresented alleles (13 and 17 repeats) but who did not possess an overrepresented allele (12 and 14 repeats) may have a lower risk of developing Achilles tendon injuries (odds ratio, 6.2; 95% confidence interval, 3.5-11.0; P <. 001). Conclusions The guanine-thymine dinucleotide repeat polymorphism within the tenascin-C gene is associated with Achilles tendon injury. Alleles containing 12 and 14 guanine-thymine repeats were overrepresented in subjects with tendon injuries, while the alleles containing 13 and 17 repeats were underrepresented. Clinical Relevance Persons who have variants of the tenascin-C gene with 12 and 14 guanine-thymine repeats appear to have a 6-fold risk of developing Achilles tendon injuries.

The COL5A1 Gene Is Associated With Increased Risk of Anterior Cruciate Ligament Ruptures in Female Participants

Background Anterior cruciate ligament ruptures, especially to young female athletes, are a cause of major concern in the sports medicine fraternity. The major structural constituents of ligaments are collagens, specifically types I and V. Recently, the gene that encodes for the α1 chain of type I collagen (COL1A1) has been shown to be associated with an increased risk of cruciate ligament ruptures. The COL5A1 gene, which encodes for the α1 chain of type V collagen, has been shown to be associated with Achilles tendon injuries. Purpose The study was conducted to determine (1) if 2 sequence variants (BstUI and DpnII restriction fragment length polymorphisms [RFLPs]) within the COL5A1 gene are associated with an increased risk of anterior cruciate ligament ruptures, and (2) if there were any gender-specific positive associations between the 2 COL5A1 sequence variants and risk of anterior cruciate ligament ruptures. Study Design Case control study; Level of evidence, 3. Methods A total of 129 white participants (38 women) with surgically diagnosed anterior cruciate ligament ruptures and 216 physically active control participants (84 women) without any history of ACL injury were included in this case-control genetic association study. All participants were genotyped for the COL5A1 BstUI and DpnII RFLPs. Results There was a significant difference in the BstUI RFLP genotype frequency between the anterior cruciate ligament rupture and physically active control groups among the female participants, but not the male participants. The CC genotype in the female participants was significantly underrepresented in the anterior cruciate ligament rupture group compared with the controls (27.4% vs 5.6%; odds ratio = 6.6; 95% confidence interval, 1.5–29.7; P = .006). There were no differences in the DpnII RFLP genotype distributions between the anterior cruciate ligament rupture and physically active control groups. Conclusion The CC genotype of the COL5A1 BstUI RFLP was underrepresented in female participants with anterior cruciate ligament ruptures. Clinical Relevance This is the first study to show that there is a specific genetic risk factor associated with risk of anterior cruciate ligament ruptures in female athletes.

Variants within the COL5A1 gene are associated with Achilles tendinopathy in two populations

Objectives: A COL5A1 gene variant was shown to be associated with chronic Achilles tendinopathy in a South African population. The aim of this case–control genetic association study was to investigate the BstUI and DpnII restriction fragment length polymorphisms (RFLP) in a second population from Australia and to identify a predisposing haplotype for Achilles tendinopathy in both populations. Methods: 85 Australian and 93 South African patients with tendinopathy, as well as 210 Australian and 132 white South African control subjects were genotyped for the BstUI (rs12722) and DpnII (rs13946) RFLP, as well as markers rs10858286, rs3196378, rs11103544, rs4504708 and rs3128575. Results: The BstUI RFLP (p<0.001) and marker rs3196378 (p = 0.016) were associated with chronic Achilles tendinopathy in Australian subjects. Individuals within both populations with a CC genotype for the BstUI RFLP had a significantly decreased risk of developing tendinopathy versus any other genotypes (Australian odds ratio 0.42, 95% CI 0.20 to 0.86, p = 0.017). The TC inferred haplotype (rs12722, rs3196378) was found to be overrepresented (global p = 0.008) in the South African tendinopathy group compared with all other haplotypes. Conclusion: The BstUI RFLP is associated with chronic Achilles tendinopathy in a second population and a region within the COL5A1 3′ untranslated region may predispose individuals to an increased risk of developing chronic Achilles tendinopathy.

Genetic risk factors for anterior cruciate ligament ruptures: COL1A1 gene variant

Background: Anterior cruciate ligament (ACL) ruptures are considered the most severe injury sustained in sports. Although various intrinsic and extrinsic risk factors have been identified, the exact aetiology of the injury is not yet fully understood. Recently, the gene encoding for the α1 chain of type I collagen (COL1A1) has been shown to be associated with cruciate ligament ruptures and shoulder dislocations. Objective: To determine whether the functional Sp1 binding site polymorphism within intron 1 of the COL1A1 gene is associated specifically with ACL ruptures in an independent population. Methods: 117 Caucasian participants with surgically diagnosed ACL ruptures, and 130 Caucasian physically active controls without any history of previous ligament or tendon injuries were recruited for this case–control genetic association study. All participants were genotyped for the COL1A1 Sp1 binding site polymorphism (G/T; rs1800012). Results: The rare TT genotype was significantly (p = 0.031, OR = 0.08, 95% CI <0.01 to 1.46) under-represented in the ACL group (0 out of 117, 0%), compared with the controls (6 out of 130, 4.6%). Conclusion: The TT genotype of the COL1A1 Sp1 binding site polymorphism was significantly under-represented in South African participants with ACL ruptures. We propose that this sequence variant be the first specific genetic element to be included in multifactorial models developed to understand the aetiology and risk factors for ACL rupture.

Tendon and ligament injuries: the genetic component

Tendons and ligaments within the upper and lower limbs are some 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. More recently, studies have suggested that there is also, at least in part, a genetic component to the Achilles tendon, rotator cuff and anterior cruciate ligament injuries. However, specific genes have not been suggested to be associated with rotator cuff or anterior cruciate ligament injuries. Sequence variants of the tenascin C (TNC) gene, on the other hand, have been shown to be associated with Achilles tendinopathies and Achilles tendon ruptures, whereas a variant of the collagen V α 1 (COL5A1) gene has also been shown to be associated with Achilles tendinopathies. Both genes encode for important structural components of tendons and ligaments. The COL5A1 gene encodes for a component of type V collagen, which has an important role in regulating collagen fibre assembly and fibre diameters. The TNC gene, on the other hand, encodes for TNC, which regulates the tissue’s response to mechanical load. To date, only variants in two genes have been shown to be associated with Achilles tendon injuries. In addition, although specific genes have not been identified, investigators have suggested that there is also a genetic component to both rotator cuff and anterior cruciate ligament injuries. In future, specific genotypes associated with increased risk of injury to specific tendons and ligaments can prevent these injuries by identifying individuals at higher risk.

The association between the COL12A1 gene and anterior cruciate ligament ruptures

Background Anterior cruciate ligament (ACL) ruptures are among the most severe musculoskeletal soft tissue injuries. However, the exact mechanisms which cause these acute injuries are unknown. Recently, sequence variants within two genes, namely COL1A1 and COL5A1, which code for the α1 chains of types I and V collagen respectively, were shown to be associated with ACL ruptures. Type XII collagen, similarly to types I and V collagen, is a structural component of the ligament fibril and is encoded by a single gene, COL12A1. Objective The aim of this study was to investigate whether sequence variants within COL12A1 are associated with ACL ruptures. Methods One hundred and twenty-nine (38 female) participants with clinically and surgically diagnosed ACL ruptures, as well as 216 (83 female) physically active controls participants (CON) without any history of ACL injury were included in this case-control genetic association study. All participants were genotyped for the AluI and BsrI restriction fragment length polymorphisms (RFLPs) within COL12A1. Results The AA genotype of the COL12A1 AluI RFLP was significantly over-represented in the female (OR=2.4, 95% CI 1.0 to 5.5, p=0.048), but not male (p=0.359) ACL participants. There were no genotype differences between the ACL and CON group for the BsrI RFLP. Conclusion The COL12A1 AluI RFLP is associated with ACL ruptures among female participants in this study. The results suggest that females with an AA genotype are at increased risk of ACL ruptures. These initial genetic association studies should be explored further and, if repeated, incorporated into multifactorial models developed to identify predisposed individuals.

Risk factors for sports concussion: an evidence-based systematic review

Concussion is a common sports injury with approximately 1.6–3.8 million sport-related concussions reported in the USA annually. Identifying risk factors may help in preventing these injuries. This systematic review aims to identify such risk factors. Three electronic databases; ScienceDirect, PubMed and SpringerLink, were searched using the keywords ‘RISK FACTORS’ or ‘PREDISPOSITION’ in conjunction with ‘SPORT’ and ‘CONCUSSION’. Based on the inclusion and exclusion criteria, 13 628 identified titles were independently analysed by two of the authors to a final list of 86 articles. Only articles with a level of evidence of I, II and III were included according to robust study design and data analysis. The level of certainty for each risk factor was determined. A high level of certainty for increased risk of a subsequent concussion in athletes sustaining more than one previous concussion was reported in 10 of 13 studies. Further, a high level of certainty was assigned to match play with all 29 studies reporting an increased concussion risk during matches. All other risk factors were evaluated as having a low level of certainty. Although several risk factors were identified from the appraised studies, prospective cohort studies, larger sample sizes, consistent and robust measures of risk should be employed in future research.

No Association of the ACTN3 Gene R577X Polymorphism with Endurance Performance in Ironman Triathlons

Alpha‐actinins are major structural components of the Z‐discs in skeletal muscle. Alpha‐actinin 3 is encoded by the ACTN3 gene and is expressed only in type II muscle fibres. Homozygosity for the nonsense mutation, 577X, within ACTN3 results in deficiency of α‐actinin‐3 but does not result in an abnormal muscular phenotype. Previous research has found an association of the 577R allele with sprinting and/or power performance. It has also been suggested that the 577X allele may confer an advantage during endurance events. Four hundred and fifty seven Caucasian male triathletes who completed either the 2000 and/or 2001 226 km South African Ironman Triathlons, and 143 Caucasian controls, were genotyped for the R577X mutation within the ACTN3 gene. There were no significant differences in either the genotype (P = 0.486) or allele (P = 0.375) frequencies within the fastest, middle of the field or slowest Caucasian male finishers and the control population. In conclusion, the R577X polymorphism within the ACTN3 gene was not associated with ultra‐endurance performance in the 2000 and 2001 South African Ironman Triathlons.

Investigation of the Sp1-binding site polymorphism within the COL1A1 gene in participants with Achilles tendon injuries and controls

Sequence variants within the type V collagen (COL5A1) and tenascin C (TNC) genes have to date been shown to be associated with chronic Achilles tendinopathies and/or spontaneous Achilles tendon ruptures. Type V collagen and tenascin C are quantitatively minor components of tendon, while type I collagen is the major structural component. There is increased expression of the COL1A1 gene, which encodes for the alpha1 chain of type I collagen, in the painful Achilles tendon. A functional Sp1-binding site polymorphism (SNP rs1800012; IVS1+1023G>T) within this gene has been shown to be associated with several connective tissue disorders. The aim of this study was to determine whether the Sp1-binding site polymorphism within the COL1A1 gene is associated with chronic Achilles tendinopathies and/or spontaneous Achilles tendon ruptures. Achilles tendinopathy (n=85), Achilles rupture (n=41) and asymptomatic control (n=125) participants were genotyped for the COL1A1 Sp1-binding site polymorphism. There were no observed statistical differences in the genotype (p=0.602) or allele (p=0.694) distributions between the groups. In conclusion, this study has shown that there is no association between the Sp1-binding site polymorphism within the first intron of COL1A1 and Achilles tendinopathy or Achilles tendon rupture within the population studied.

The COL5A1 genotype is associated with range of motion measurements

There is an interest in identifying the intrinsic risk factors, including altered musculotendinous flexibility, that may be associated with musculotendinous injuries. We have recently shown that a sequence variant, namely the BstUI restriction fragment length polymorphism (RFLP), within the COL5A1 gene is associated with chronic Achilles tendinopathy. Mutations within COL5A1 have been implicated in Ehlers Danlos syndrome, a condition that is characterized by joint hypermobility. The aim of this study was to investigate the association of sequence variants within COL5A1 and musculotendinous range of motion (ROM). The sit and reach (SR) and the passive straight leg raise (SLR) were measured on 119 Caucasian subjects with either a past, current or no history of Achilles tendon injuries. The subjects were genotyped for four sequence variants within the 3′‐UTR of the COL5A1 gene. Gender (P=0.016), age (P=0.011) and the BstUI RFLP (P=0.010) jointly contributed significantly to the optimal SLR model which accounted for 19.3% of the variance. The factors contributing significantly to SR, which accounted for 28.8% of the variance, were weight (P=0.004), age (P<0.001) and the BstUI RFLP (P=0.001). These data suggest that the COL5A1 BstUI RFLP is independently associated with lower limb ROM within the cohort investigated in this study.