Michael Posthumus

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.

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.

The COL1A1 gene and acute soft tissue ruptures

Three studies have suggested that the rare TT genotype of the functional Sp1 binding site polymorphism within intron 1 of COL1A1 is associated with cruciate ligament ruptures (CL), shoulder dislocations (SD) and/or Achilles tendon ruptures. Similar genotype distributions were reported for the control and the injury groups in all three studies. In this report, the data from these studies were combined and analyzed. The TT genotype, when compared to the control group (4.1%, n=24 of 581), was significantly under-represented in the (1) CL (0.3%, n=1 of 350, OR=15.0, P=0.0002), (2) CL and SD (0.4% TT genotype, n=2 of 476, OR=10.2, P<0.0001), and (3) CL, SD and Achilles tendon ruptures (0.4% TT genotype, n=2 of 517, OR=11.1, P<0.0001) groups. This combined analysis indicates that the TT genotype appears to be protective against acute soft tissue ruptures and should be incorporated into multifactorial models determining risk of acute soft tissue ruptures.

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.

Matrix metalloproteinase genes on chromosome 11q22 and the risk of anterior cruciate ligament (ACL) rupture.

As matrix metalloproteinases (MMPs) are critical to ligament homeostasis and integrity, the aim of this study was to investigate whether four functional polymorphisms within four MMP genes, which cluster on chromosome 11q22 associate with risk of ACL ruptures. Three hundred and forty‐five [129 with ACL ruptures (ACL group) and 216 asymptomatic controls (CON group)] unrelated Caucasians were recruited for this case‐control study. Fifty‐four participants reported non‐contact mechanisms of ACL rupture (NON subgroup). All participants were genotyped for the MMP10 C/T rs486055, MMP1 1G/2G rs1799750, MMP3 G/A rs679620 and MMP12 A/G rs2276109 variants. After adjusting for sex, age and weight, the AG and GG genotypes of the MMP12 rs2276109 variant were significantly (P=0.030) under‐represented among the NON subgroup (14%), when compared with the CON group (26%). No other variants were significantly different between groups. Adjusted for the same confounders, the two four‐variant haplotypes T‐1G‐A‐A (CON 14%, ACL 9%, P=0.033) and C‐2G‐G‐G (CON 14%, NON 5%, P=0.021) were significantly different between the CON and the ACL groups, and the CON group and the NON subgroup, respectively. This is the first report that indicates an association between the chromosomal region 11q22 and the risk of ACL rupture.

Type V Collagen Genotype and Exercise-Related Phenotype Relationships: A Novel Hypothesis

We have shown that a variant within COL5A1, which encodes a subunit of type V collagen, is associated with injury and performance phenotypes. Although seemingly unrelated, these phenotypes are associated directly or indirectly with the mechanical properties of musculoskeletal soft tissue. We therefore hypothesize that variants in the COL5A1 gene alter fibril architecture and structure and, thereby, mechanical properties.

The Intrinsic Risk Factors for ACL Ruptures: An Evidence-Based Review

Abstract This article aims to assess the evidence related to the intrinsic risk factors for anterior cruciate ligament (ACL) ruptures. The level of evidence (according to evidence-based guidelines) for each study and the level of certainty for each risk factor were determined. After a review of the evidence, femoral notch geometry was the only risk factor that was found to be associated with risk of ACL rupture with high certainty. This review concludes that more research, particularly high-quality, prospective studies, are required to provide accurate measures of risk. These data should be used to establish multifactorial risk factor models designed to identify individuals at high risk of sustaining an ACL injury.

The COL5A1 gene: a novel marker of endurance running performance.

BACKGROUND Running economy, a key component of endurance ability, has been shown to be associated with flexibility. Increased stiffness (inflexibility) may improve running economy and therefore endurance running ability. The COL5A1 gene, which encodes the α1-chain of type V collagen, was found to associate with measures of flexibility. Type V collagen is a quantitatively minor fibrillar collagen, which is believed to regulate fibrillogenesis within tendons and other connective tissue. PURPOSE The aim of this study was therefore to determine whether the COL5A1 gene is associated with endurance performance. METHODS Three hundred thirteen Caucasian male participants who completed either the 2006 or the 2007 226-km South African Ironman triathlon (3.8-km swim, 180-km bike, and 42.2-km run) participated in this study. All participants were genotyped for the COL5A1 BstUI restriction fragment length polymorphism (RFLP). RESULTS The COL5A1 BstUI RFLP was significantly associated with time to complete the running component of the triathlon. Participants with a TT genotype completed the running component of the race significantly faster than individuals with a CC genotype (P = 0.019; mean ± SD: TT = 294.2 ± 52.1 min, CC = 307.4 ± 48.6 min). In addition, there was a significant linear trend (P = 0.020) in the CC genotype distribution when the run times were divided into the fastest (13%), middle (17%), and slowest (25%) tertiles. There were no significant genotype differences for time to complete the swim, the bike, or the overall race. COL5A1 BstUI RFLP, body mass index, age, and 15 wk of running training history predicted 30% of the variance in running performance. CONCLUSION This is the first study to identify the COL5A1 BstUI RFLP as a marker for endurance running performance. Further studies are required to replicate these findings.

The association of genes involved in the angiogenesis‐associated signaling pathway with risk of anterior cruciate ligament rupture

Angiogenesis‐associated signaling is a fundamental component in the remodeling of the extracellular matrix in response to loading. Genes encoding protein components within this signaling cascade are therefore suitable candidates for investigation into ACL injury susceptibility: namely, vascular endothelial growth factor A isoform (VEGFA), kinase insert‐domain receptor (KDR), nerve growth factor (NGF), and hypoxia inducible factor‐1α (HIF1A). A case‐control genetic association study was conducted on 227 asymptomatic control participants and 227 participants with surgically diagnosed ACL ruptures of which 126 participants reported a non‐contact mechanism of rupture. All participants were genotyped for seven polymorphisms within the four genes. The VEGFA rs699947 CC genotype (p = 0.010, OR: 1.92, 95% CI: 1.17–3.17) was significantly over‐represented within participants with non‐contact ACL ruptures. The VEGFA rs1570360 GA genotype was significantly over‐represented in the CON group (p = 0.007, OR: 1.70, 95% CI: 1.16–2.50). Furthermore, the KDR rs2071559 GA genotype was significantly over‐represented in the female controls (p = 0.023, OR: 2.16, 95% CI: 1.11–4.22). Inferred haplotype analyses also implicated genomic regions spanning the VEGFA and KDR genes. These novel findings suggest that regions within VEGFA and KDR may be implicated in the pathophysiology of ACL ruptures; highlighting the potential biological significance of angiogenesis‐associated signaling in the aetiology of ACL ruptures.