Investigation of multiple populations highlight VEGFA polymorphisms to modulate anterior cruciate ligament injury.

Polymorphisms in VEGFA and KDR encoding proteins have been associated with anterior cruciate ligament (ACL) injury risk. We leveraged a collective sample from Sweden, Poland, and Australia to investigate the association of functional polymorphisms in VEGFA and KDR with susceptibility to ACL injury risk. Using a case-control genetic association approach, polymorphisms in VEGFA and KDR were genotyped and haplotypes inferred from 765 controls, and 912 cases clinically diagnosed with ACL rupture. For VEGFA, there was a significant overrepresentation of the rs2010963 CC genotype (p = 0.0001, false discovery rate [FDR]: p = 0.001, odds ratio [OR]: 2.16, 95% confidence interval [CI]: 1.47-3.19) in the combined ACL group (18%) compared to the combined control group (11%). The VEGFA (rs699947 C/A, rs1570360 G/A, rs2010963 G/C) A-A-G haplotype was significantly (p = 0.010, OR: 0.85, 95% CI: 0.69-1.05) underrepresented in the combined ACL group (23%) compared to the combined control group (28%). In addition, the A-G-G construct was significantly (p = 0.036, OR: 0.81, 95% CI: 0.64-1.02) underrepresented in the combined ACL group (12%) compared to the combined CON group (16%). Our findings support the association of the VEGFA rs2010963 CC genotype with increased risk and (ii) the VEGFA A-A-G haplotype with a reduced risk, and are in alignment with the a priori hypothesis. Collectively identifying a genetic interval within VEGFA to be implicated in ACL risk modulation and highlight further the importance of vascular regulation in ligament biology.

Risk modelling further implicates the angiogenesis pathway in anterior cruciate ligament ruptures.

The aim of this study was to explore the interactions between the interleukins and the angiogenesis signalling pathway, following a pathway-based approach. Statistical modelling tools were used to develop a preliminary polygenic risk assessment model for anterior cruciate ligament (ACL) ruptures, incorporating the angiogenesis signalling genes (VEGFA and KDR) and interleukins (IL1B, IL6, IL6R) which also function to regulate angiogenesis. Multivariate logistic regression analysis was used to identify the most informative contributors to ACL rupture risk from a range of eleven potential intrinsic risk factors: age, sex, BMI and eight genetic polymorphisms within five genes, namely, IL1B rs16944 C/T, IL6 rs1800795 G/C, IL6R rs2228145 C/A, VEGFA rs699947 C/A, VEGFA rs1570360 G/A, VEGFA rs2010963 C/G, KDR rs2071559 A/G and KDR rs1870377 T/A. A total of 232 asymptomatic controls (CON) and 234 participants with surgically diagnosed ACL ruptures, of which 135 participants reported a non-contact mechanism of injury (NON subgroup), were previously genotyped for the selected polymorphisms. The polygenic risk model identified the VEGFA rs699947 CC genotype (p = 0.024, odds ratio (OR): 3.35, 95% confidence interval (CI): 1.17-9.62), VEGFA rs2010963 GC genotype (p = 0.049, OR: 2.43, 95% CI: 1.00-5.87), age (p = 0.011, OR: 0.97, 95% CI: 0.95-0.99) and BMI (p = 0.009, OR:1.09, 95% CI: 0.57-2.11) as the most significant predictors of ACL rupture risk from the data included. The results of this study highlight VEGFA, age and BMI as biologically significant components of this network requiring further investigation in the context of musculoskeletal soft tissue injury risk.HighlightsThe findings of this study highlight the VEGFA gene, age and BMI as biologically significant contributors to ACL rupture susceptibility.Upon further validation of these risk factors, they may be included in genetic risk assessment tools to design pre-habilitation strategies, prescribe appropriate treatment strategies after injury or to assess how an individual is likely to respond to load.Polygenic risk models aid in highlighting the components of the complex ECM remodelling pathway requiring further investigation, using a multidisciplinary approach.VEGFA is a key angiogenic protein contributing to ECM homeostasis and may therefore have potential therapeutic implications that need to be explored.

More than a Metric: How Training Load is Used in Elite Sport for Athlete Management.

Training load monitoring is a core aspect of modern-day sport science practice. Collecting, cleaning, analysing, interpreting, and disseminating load data is usually undertaken with a view to improve player performance and/or manage injury risk. To target these outcomes, practitioners attempt to optimise load at different stages throughout the training process, like adjusting individual sessions, planning day-to-day, periodising the season, and managing athletes with a long-term view. With greater investment in training load monitoring comes greater expectations, as stakeholders count on practitioners to transform data into informed, meaningful decisions. In this editorial we highlight how training load monitoring has many potential applications and cannot be simply reduced to one metric and/or calculation. With experience across a variety of sporting backgrounds, this editorial details the challenges and contextual factors that must be considered when interpreting such data. It further demonstrates the need for those working with athletes to develop strong communication channels with all stakeholders in the decision-making process. Importantly, this editorial highlights the complexity associated with using training load for managing injury risk and explores the potential for framing training load with a performance and training progression mindset.

Functional COL1A1 variants are associated with the risk of acute musculoskeletal soft tissue injuries.

Studies have reported the association of the COL1A1 Sp1 binding site variant (rs1800012) with the risk of acute musculoskeletal soft tissue injuries. Interaction with the COL1A1 promoter variant (rs1107946) has also been proposed to modulate acute injury risk. Conversely, neither of these loci have been associated with chronic musculoskeletal soft tissue phenotypes. Therefore, the primary aim of this study involved characterizing these variants in a cohort of participants with chronic Achilles tendinopathy. Second, this study aimed to support the contribution of the rs1107946 and rs1800012 variants to the profile predisposing for acute musculoskeletal soft tissue injuries including Achilles tendon and anterior cruciate ligament (ACL) ruptures. A hypothesis-driven association study was conducted. In total, 295 control participants, 210 participants with clinically diagnosed Achilles tendinopathy, and 72 participants with Achilles tendon ruptures recruited independently from South Africa and the United Kingdom were genotyped for the prioritized variants. In addition, a cohort including 232 control participants and 234 participants with surgically diagnosed ACL ruptures was also analyzed. Although no associations were observed in the recruited cohorts, the rare rs1800012 TT genotype was associated with decreased ACL injury risk when the results from the current study were combined with that from previously published studies (P = .040, OR: 2.8, 95% CI: 1.0-11.0). In addition, the G-T (rs1107946-rs1800012) inferred haplotype was associated with decreased risk for Achilles tendon ruptures. These results support previous observations and reiterate the heterogeneity of musculoskeletal phenlotypes whereby certain markers may be common to the predisposing profiles while others may be unique.

Characterisation of Achilles tendon pain in recreational runners using multidimensional pain scales.

OBJECTIVES: The main assessment tool for Achilles tendinopathy (AT) is the VISA-A. However, the VISA-A only assesses the physical impairments that result from tendon pain. This study sought to describe and assess tendon pain using other multidimensional pain scales; the short forms of the McGill pain questionnaire (sf-MPQ) and the Brief Pain Inventory (sf-BPI). DESIGN: Cross sectional observational study. METHODS: 124 recreational runners with clinically confirmed mid-portion Achilles tendinopathy for at least 3 months were recruited from Cape Town, South Africa. They described and rated their tendinopathy symptoms by completing the VISA-A, sf-BPI and sf-MPQ questionnaires. RESULTS: Tendon pain was largely described as a sensory type of pain with minimal affective elements. Sixty percent described their pain as aching. Significant proportions described it as tender (52.9%), throbbing (33.9%), hot burning (24.8%) and 33.8% ranked it as discomfiting or worse on the pain intensity score of the sf-MPQ. Tendon pain interfered with mood in 50.8% of the participants as well as with walking ability (72.5%), sleep (34.8%) and enjoyment of life (54.2%). CONCLUSIONS: Tendon pain was described using a variety of adjectives which may suggest that AT has clinical subtypes. Tendon pain interferes with more than just physical function. Therefore, the recommendation is to conduct further studies using various pain questionnaires to elicit more details and better understand the nature of Achilles tendon pain.

The Apoptosis Pathway and CASP8 Variants Conferring Risk for Acute and Overuse Musculoskeletal Injuries.

Rotator cuff tendinopathy (RCT), anterior cruciate ligament (ACL) ruptures, and carpal tunnel syndrome (CTS), are examples of chronic (RCT and CTS) and acute (ACL ruptures) musculoskeletal soft tissue injuries. These injuries are multifactorial in nature, with several identified intrinsic and extrinsic risk factors. Previous studies have implicated specific sequence variants within genes encoding structural and regulatory components of the extracellular matrix of tendons and/ligaments to predispose individuals to these injuries. An example, includes the association of sequence variants within the apoptotic regulatory gene, caspase-8 (CASP8) with other musculoskeletal injury phenotypes, such as Achilles tendinopathy. The primary aim of this study was, therefore, to investigate previously implicated DNA sequence variants within CASP8: rs3834129 (ins/del) and rs1045485 (G/C), and the rs13113 (T/A) identified using a whole exome sequencing approach, with risk of musculoskeletal injury phenotypes (RCT, ACL ruptures, and CTS) in three independent studies. In addition, the aim was to implicate a CASP8 genomic interval in the modulation of risk of RCT, ACL ruptures, or CTS. It was found that the AA genotype of CASP8 rs13113 (T/A) was independently associated with increased risk for CTS. In addition, it was found that the del-C haplotype (rs3834129-rs1045485) was significantly associated with non-contact ACL ruptures, which is in alignment with previous research findings. Collectively, the results of this study implicate the apoptosis pathway as biologically significant in the underlying pathogenesis of musculoskeletal injury phenotypes. These findings should be repeated in larger sample cohorts and across different populations. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:680-688, 2020.

Functional polymorphisms within the inflammatory pathway regulate expression of extracellular matrix components in a genetic risk dependent model for anterior cruciate ligament injuries.

OBJECTIVES: To investigate the functional effect of genetic polymorphisms of the inflammatory pathway on structural extracellular matrix components (ECM) and the susceptibility to an anterior cruciate ligament (ACL) injury. DESIGN: Laboratory study, case-control study. METHODS: Eight healthy participants were genotyped for interleukin (IL)1B rs16944 C>T and IL6 rs1800795 G>C and classified into genetic risk profile groups. Differences in type I collagen (COL1A1), type V collagen (COL5A1), biglycan (BGN) and decorin (DCN) gene expression were measured in fibroblasts either unstimulated or following IL-1ß, IL-6 or tumor necrosis factor (TNF)-α treatment. Moreover, a genetic association study was conducted in: (i) a Swedish cohort comprised of 116 asymptomatic controls (CON) and 79 ACL ruptures and (ii) a South African cohort of 100 CONs and 98 ACLs. Participants were genotyped for COL5A1 rs12722 C>T, IL1B rs16944 C>T, IL6 rs1800795 G>C and IL6R rs2228145 G>C. RESULTS: IL1B high-risk fibroblasts had decreased BGN (p=0.020) and COL5A1 (p=0.012) levels after IL-1ß stimulation and expressed less COL5A1 (p=0.042) following TNF-α treatment. Similarly, unstimulated IL6 high-risk fibroblasts had lower COL5A1 (p=0.012) levels than IL6 low-risk fibroblasts. In the genetic association study, the COL5A1-IL1B-IL6 T-C-G (p=0.034, Haplo-score 2.1) and the COL5A1-IL1B-IL6R T-C-A (p=0.044, Haplo-score: 2.0) combinations were associated with an increased susceptibility to ACL injury in the Swedish cohort when only male participants were evaluated. CONCLUSIONS: This study shows that polymorphisms within genes of the inflammatory pathway modulate the expression of structural and fibril-associated ECM components in a genetic risk depended manner, contributing to an increased susceptibility to ACL injuries.

Unravelling the interaction between the DRD2 and DRD4 genes, personality traits and concussion risk.

BACKGROUND: Concussion occurs when biomechanical forces transmitted to the head result in neurological deficits. Personality may affect the balance between safe and dangerous play potentially influencing concussion risk. Dopamine receptor D2 (DRD2) and dopamine receptor D4 (DRD4) genetic polymorphisms were previously associated with personality traits. OBJECTIVES: This case-control genetic association study investigated the associations of (1) DRD2 and DRD4 genotypes with concussion susceptibility and personality, (2) personality with concussion susceptibility and (3) the statistical model of genotype, personality and concussion susceptibility. METHODS: In total, 138 non-concussed controls and 163 previously concussed cases were recruited from high school (n=135, junior), club and professional rugby teams (n=166, senior). Participants were genotyped for DRD2 rs12364283 (A>G), DRD2 rs1076560 (C>A) and DRD4 rs1800955 (T>C) genetic variants. Statistical analyses including structural equation modelling were performed using the R environment and STATA. RESULTS: The rs1800955 CC genotype (p=0.014) and inferred DRD2 (rs12364283-rs1076560)-DRD4 (rs1800955) A-C-C allele combination (p=0.019) were associated with decreased concussion susceptibility in juniors. The rs1800955 TT and CT genotypes were associated with low reward dependence in juniors (p<0.001) and seniors (p=0.010), respectively. High harm avoidance was associated with decreased concussion susceptibility in juniors (p=0.009) and increased susceptibility in seniors (p=0.001). The model showed that a genetic variant was associated with personality while personality was associated with concussion susceptibility. CONCLUSION: These findings highlight the linear relationship between genetics, personality and concussion susceptibility. Identifying a genetic profile of 'high risk' behaviour, together with the development of personalised behavioural training, can potentially reduce concussion risk.

Toxic tau: The TAU gene polymorphisms associate with concussion history in rugby union players.

OBJECTIVES: Concussion is a brain injury that occurs when biomechanical forces are transmitted to the head region resulting in neurological deficits. The accumulation of tau protein in autopsies of athletes with multiple concussions implicates tau in concussion-associated neurodegeneration. The TAU rs2435211 (C>T) and rs2435200 (G>A) polymorphisms are involved in pathological tau expression and neurodegenerative disease risk. The aims of this study were to investigate the associations of TAU (rs2435211, rs2435200) polymorphisms with concussion history and sustaining multiple concussions in rugby. DESIGN: In total, 140 non-concussed controls and 163 previously concussed participants (all cases group, N=163; clinically diagnosed, N=140; multiple concussed, N=87) were recruited from high school (N=135, junior), club and professional rugby teams (N=166, senior). METHODS: Participants were genotyped for TAU rs2435211 and rs2435200 polymorphisms. RESULTS: In seniors, the rs2435200 AA genotype was significantly over-represented in the control group compared to the multiple concussed subgroup (P=0.033, control: 25%, N=16, multiple concussed: 11%, N=6; OR: 0.34, 95% CI 0.12-0.96). While the AG genotype was significantly under-represented in the control compared to multiple concussed (P=0.024, control: 45%, N=29, multiple concussed: 63%, N=36; OR: 2.34, 95% CI 1.11-4.95). The inferred TAU (rs2435211 C>T-rs2435200 G>A) T-G haplotype was significantly under-represented in the control (19%, N=12) compared to the all cases group (30%, N=28, P=0.031). CONCLUSIONS: The TAU-associated neurodegenerative pathway was implicated as a potential pathophysiological mechanism underlying concussion in seniors. In future, the identification of TAU polymorphisms associated with concussion risk may assist clinical management and reduce risk of severe complications.

Inflammatory and apoptotic signalling pathways and concussion severity: a genetic association study.

The objective was to investigate the relationship between IL-1B rs16944, IL-6 rs1800795, and CASP8 rs3834129 genetic polymorphisms and concussion severity. Rugby players from high school, senior amateur, and professional teams completed a concussion severity questionnaire and donated a DNA sample. Participants (n = 163) were split into symptom severity groups around the median number and duration of symptoms. The frequency of participants with high symptom counts (more than five symptoms) increased across the IL-1B (C/C: 35%; C/T: 51%; T/T: 56%; P = 0.047) and the IL-6 (C/C: 31%; C/G: 44%; G/G: 58%; P = 0.027) genotypes. The C-C inferred interleukin allele construct frequency, created from combining the IL-1B and IL-6 genotype data, was lower in participants reporting a high symptom count (18%), compared to those with a low symptom count (fewer than six symptoms, 36%, P = 0.002). Similarly, the C-C inferred interleukin allele construct frequency was lower in those reporting prolonged symptom duration (more than one week, 16%), as opposed to short symptom duration (less than one week, 34%, P = 0.015). This study provides evidence of novel inflammatory pathway genetic associations with concussion severity, which supports the hypothesis implicating neuroinflammation in the development of concussion symptoms.

The association between COMT rs4680 and 5-HTTLPR genotypes and concussion history in South African rugby union players.

The objective was to investigate the relationship between Catechol-O-methyltransferase (COMT) rs4680 and serotonin-transporter-linked polymorphic region (5-HTTLPR) genotypes with concussion history and personality traits. Rugby players ("all levels": n = 303), from high schools ("junior", n = 137), senior amateur, and professional teams ("senior", n = 166), completed a self-reported concussion history questionnaire, Cloninger's Tridimensional Personality Questionnaire, and donated a DNA sample. Participants were allocated into control (non-concussed, n = 140), case (all) (previous suspected or diagnosed concussions, n = 163), or case (diagnosed only) (previous diagnosed concussion, n = 140) groups. COMT rs4680 Val/Val genotypes were over-represented in controls in all levels (P = 0.013, OR:2.00, 95% CI:1.15-3.57) and in juniors (P = 0.003, OR:3.57, 95% CI:1.45-9.09). Junior Val/Val participants displayed increased "anticipatory worry" (P = 0.023). The 5-HTTLPR low expressing group was under-represented in controls when all levels were considered (P = 0.032; OR:2.02, 95% CI:1.05-3.90) and in juniors (P = 0.021; OR:3.36, 95% CI:1.16-9.72). Junior 5-HTTLPR low and intermediate expressing groups displayed decreased "harm avoidance" (P = 0.009), "anticipatory worry" (P = 0.041), and "fear of uncertainty" (P < 0.001). This study provides preliminary indications that personality associated genetic variants can influence concussion in rugby.

A multilayer biomaterial for osteochondral regeneration shows superiority vs microfractures for the treatment of osteochondral lesions in a multicentre randomized trial at 2 years.

PURPOSE: The increasing awareness on the role of subchondral bone in the etiopathology of articular surface lesions led to the development of osteochondral scaffolds. While safety and promising results have been suggested, there are no trials proving the real potential of the osteochondral regenerative approach. Aim was to assess the benefit provided by a nanostructured collagen-hydroxyapatite (coll-HA) multilayer scaffold for the treatment of chondral and osteochondral knee lesions. METHODS: In this multicentre randomized controlled clinical trial, 100 patients affected by symptomatic chondral and osteochondral lesions were treated and evaluated for up to 2 years (51 study group and 49 control group). A biomimetic coll-HA scaffold was studied, and bone marrow stimulation (BMS) was used as reference intervention. Primary efficacy measurement was IKDC subjective score at 2 years. Secondary efficacy measurements were: KOOS, IKDC Knee Examination Form, Tegner and VAS Pain scores evaluated at 6, 12 and 24 months. Tissue regeneration was evaluated with MRI MOCART scoring system at 6, 12 and 24 months. An external independent agency was involved to ensure data correctness and objectiveness. RESULTS: A statistically significant improvement of all clinical scores was obtained from basal evaluation to 2-year follow-up in both groups, although no overall statistically significant differences were detected between the two treatments. Conversely, the subgroup of patients affected by deep osteochondral lesions (i.e. Outerbridge grade IV and OCD) showed a statistically significant better IKDC subjective outcome (+12.4 points, p = 0.036) in the coll-HA group. Statistically significant better results were also found for another challenging group: sport active patients (+16.0, p = 0.027). Severe adverse events related to treatment were documented only in three patients in the coll-HA group and in one in the BMS group. The MOCART score showed no statistical difference between the two groups. CONCLUSIONS: This study highlighted the safety and potential of a biomimetic implant. While no statistically significant differences were found compared to BMS for chondral lesions, this procedure can be considered a suitable option for the treatment of osteochondral lesions. LEVEL OF EVIDENCE: I.

The association between harm avoidance personality traits and self-reported concussion history in South African rugby union players.

OBJECTIVES: Personality traits have been proposed to affect the risk of sports concussion, but evidence is limited. Cloninger's Tridimensional Personality Questionnaire (TPQ) measures novelty seeking, harm avoidance (HA), and reward dependence traits. The aim of this study was to investigate the relationship between TPQ scores and concussion history in rugby union players. DESIGN: Cross-sectional study. METHODS: Rugby players from high schools, senior amateur clubs, and professional teams provided a self-reported concussion history and completed the TPQ. Participants reporting no previous concussions formed the control group, while participants reporting concussion formed the case group. A one-way analysis of covariance, with age as a covariate, was used to examine the differences in TPQ scores between groups. RESULTS: Of the 309 participants, 54% reported a minimum of one concussion (junior: 47%; amateur: 52%; professional: 72%). HA scores were significantly higher in junior players without a history of concussion compared to cases (p=0.006). Specifically, the junior control group had higher "anticipatory worry" (p=0.009) and "fear of uncertainty" (p=0.008). In contrast, the professional control group had lower HA scores than cases (p=0.009), while the amateur cohort displayed no differences between control and case groups. CONCLUSIONS: This study identified a novel association between HA and concussion in rugby players, adding evidence to the role of personality in a multifactorial risk-model of concussion. The findings suggest that lower HA may lead to increased dangerous play in youth rugby, influencing concussion susceptibility. Contrasting associations in the professional cohort suggest further research is required to understand the role of personality in concussion.

An association between polymorphisms within the APOE gene and concussion aetiology in rugby union players.

OBJECTIVES: Concussion refers to changes in neurological function due to biomechanical forces transmitted to the head. The APOE ε4 allele is associated with brain injury severity. The objective was to determine if APOE gene variants are associated with concussion history and severity in rugby players. DESIGN: In total, 128 non-concussed controls and 160 previously concussed participants (all cases N=160; diagnosed N=139) were recruited from high school (junior, N=121), club (N=116) and professional rugby teams (N=51). METHODS: Participants were genotyped for rs405509 (G>T), rs429358 (T>C) and rs7412 (C>T) APOE variants. Statistical analyses were performed using the R environment. RESULTS: The rs405509 TT genotype was over-represented in controls compared to all cases (P=0.043; control: 29%, all cases: 18%; odds ratio: 0.55, 95% confidence interval 0.31-0.98). The APOE-ε isoform frequencies were not significantly different between groups (P>0.05). Additionally, the inferred APOE (rs405509-ε2/ε3/ε4) T-ε3 haplotype was over-represented in controls (41%) compared to diagnosed (32%, P=0.042). The G-ε3 haplotype was under-represented in controls (36%) compared to all cases (44%, P=0.019) and diagnosed (44%, P=0.021). The TT genotype was significantly associated with rapid recovery (P=0.048, <1 week: 51%, N=70, ≥1 week: 36%, N=29; odds ratio: 0.55, 95% confidence interval 0.30-1.01). CONCLUSIONS: These findings support the further elucidation of the APOE gene or closely-related genes in concussion aetiology. Although similar preliminary results were found when juniors were separately analysed, the under-powered sample size for junior subgroup requires future investigation in larger cohorts of junior-level athletes.

Investigation of angiogenesis genes with anterior cruciate ligament rupture risk in a South African population.

The angiogenesis-signalling pathway is a physiological response after mechanical loading to promote matrix remodelling and thereby maintain tissue homeostasis. Studies have shown increased expression of angiogenic molecules in response to loading and in ruptured ligaments. Recently, polymorphisms within the vascular endothelial growth factor A (VEGFA) and kinase insert-domain receptor (KDR) genes were associated with risk of anterior cruciate ligament (ACL) ruptures and Achilles tendinopathy in Caucasian study groups. A case-control genetic association study was conducted on 100 controls and 98 participants with surgically-diagnosed ACL ruptures; of which 51 participants reported non-contact mechanism of injury (NON). All participants were genotyped for five functional polymorphisms: VEGFA (rs699947, rs1570360, rs2010963) and KDR (rs2071559, rs1870377). Haplotypes were inferred. In the male participants, the KDR rs2071559 AG genotype was significantly over-represented (P = 0.048, OR: 1.90, 95% CI: 1.00-3.59) in the controls. Furthermore, the GG genotype was significantly under-represented in the male controls compared to the male ACL group (P = 0.018, OR: 2.77, 95% CI: 1.17-6.55) and the male NON subgroup (P = 0.013, OR: 3.26, 95% CI: 1.24-8.58). Haplotype analysis implicated the KDR gene in all participants and in male participants separately. Collectively, these results implicate the angiogenesis-signalling pathway as a potentially key biological pathway contributing to ACL injury susceptibility.

Modulators of the extracellular matrix and risk of anterior cruciate ligament ruptures.

OBJECTIVES: The extracellular matrix (ECM) of ligaments continuously undergoes remodelling in order to maintain tissue homeostasis. Several key mediators of ECM remodelling were chosen for investigation in the present study. It is thought that polymorphisms within genes encoding signalling molecules may contribute to inter-individual variation in the responses to mechanical loading, potentially altering risk of injury. DESIGN: A genetic association study was conducted on 232 asymptomatic controls (CON) and 234 participants with surgically diagnosed anterior cruciate ligament (ACL) ruptures; of which 135 participants reported a non-contact mechanism of injury (NON subgroup). METHODS: All participants were genotyped for ten variants in eight genes encoding ECM remodelling proteins. Haplotypes and allele combinations were also inferred. RESULTS: The CASP8 rs3834129 ins allele was significantly over-represented in the male CON group compared to the male NON subgroup (p=0.047, OR: 1.46, 95% CI: 1.01-2.12). In female participants, the IL1B rs16944 TT genotype was significantly under-represented in the CON group compared to the NON subgroup (p=0.039, OR: 3.06, 95% CI: 1.09-8.64). Haplotype analysis revealed an under-representation of the CASP8 rs3834129-rs1045485 del-G haplotype in the CON group compared to both the ACL group (p=0.042; haplo.score:2.03) and the NON subgroup (p=0.037; haplo.score:2.09). Furthermore, following a pathway-based approach, genetic variants involved in the cell signalling cascade were associated with ACL injury risk. CONCLUSIONS: The novel independent associations and allele combinations observed implicate the apoptosis and cell signalling cascades as potential contributors to ACL injury susceptibility. Furthermore, these genetic variants may potentially modulate ECM remodelling in response to loading and ultimately contribute to ligament capacity.

Polymorphisms within the COL5A1 gene and regulators of the extracellular matrix modify the risk of Achilles tendon pathology in a British case-control study.

Several genetic loci have been associated with risk of Achilles tendon pathology (ATP) within South African and Australian populations. The aim of this study was, therefore, to evaluate eight previously implicated genetic variants in an independent British population. A total of 130 asymptomatic controls (CON) and 112 participants clinically diagnosed with ATP comprising 87 individuals with chronic Achilles tendinopathy (TEN) and 25 with Achilles tendon ruptures (RUP) were included. All participants were genotyped for variants within the COL5A1, MIR608, IL-1ß, IL-6 and CASP8 genes. Primary findings implicated COL5A1 and CASP8. Three inferred allele combinations constructed from COL5A1 rs12722, rs3196378 and rs71746744 were identified as risk modifiers. The T-C-D combination was associated with increased risk of ATP (P = 0.023) and RUP (P < 0.001), the C-A-I combination was associated with increased risk of ATP (P = 0.011), TEN (P = 0.011) and RUP (P = 0.011) and the C-C-D combination was associated with decreased risk of ATP (P = 0.011) and RUP (P = 0.004). The CASP8 rs3834129 DD genotype was associated with decreased risk of TEN (P = 0.020, odds ratio: 0.45, 95% confidence interval: 0.22-0.90) and the CASP8 I-G (rs3834129-rs1045485) inferred allele combination was associated with increased risk of TEN (P = 0.031). This study further highlights the importance of polymorphisms within COL5A1 and CASP8 in the aetiology of ATP.

Human Genetic Variation, Sport and Exercise Medicine, and Achilles Tendinopathy: Role for Angiogenesis-Associated Genes.

Sport and Exercise Medicine is one of the important subspecialties of 21st century healthcare contributing to improving the physical function, health, and vitality of populations while reducing the prevalence of lifestyle-related diseases. Moreover, sport and exercise are associated with injuries such as Achilles tendinopathy, which is a common tendon injury. The angiogenesis-associated signaling pathway plays a key role in extracellular matrix remodeling, with increased levels of angiogenic cytokines reported after cyclic stretching of tendon fibroblasts. We investigated the variants in angiogenesis genes in relation to the risk of Achilles tendinopathy in two population samples drawn independently from South Africa (SA) and the United Kingdom (UK). The study sample comprised 120 SA and 130 UK healthy controls, and 108 SA and 87 UK participants with Achilles tendinopathy. All participants were genotyped for five functional polymorphisms in the vascular endothelial growth factor, A isoform (VEGFA) (rs699947, rs1570360, rs2010963) and kinase insert-domain receptor (KDR) genes (rs1870377, rs2071559). The VEGFA A-G-G inferred haplotype was associated with an increased risk of Achilles tendinopathy in the SA group (15% in controls vs. 20% in cases, p = 0.048) and the combined SA+UK group (14% in controls vs. 20% in cases, p = 0.009). These new findings implicate the VEGFA gene with Achilles tendinopathy risk, while highlighting the potential biological significance of the angiogenesis signaling pathway in the etiology of Achilles tendinopathy. The evidence suggesting a genetic contribution to the susceptibility of sustaining a tendon injury is growing. We anticipate that high-throughput and multi-omics approaches, building on genomics, proteomics, and metabolomics, may soon uncover the pathophysiology of many diseases in the field of Sports and Exercise Medicine, as a new frontier of global precision medicine.

Incidence and Factors Associated With Concussion Injuries at the 2011 to 2014 South African Rugby Union Youth Week Tournaments.

OBJECTIVE: To determine the concussion incidence and to identify factors associated with concussion in South African youth rugby union players. DESIGN: Prospective cohort study. SETTING: Injury surveillance was completed at the South African Rugby Union Youth Week tournaments (under-13, under-16, and under-18 age groups). PARTICIPANTS: South African youth rugby union players. A total of 7216 players participated in 531 matches between 2011 and 2014. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Concussion incidence was calculated per 1000 player-match-hours with 95% CIs. Poisson regression was used to calculate the incidence rate ratio (IRR) between factors (age, time period, playing position, and activity at the time of concussion) potentially associated with concussions. RESULTS: The concussion incidence was 6.8/1000 player-match-hours (95% CI, 5.5-8.1) across all age groups. Under-13s (IRR, 1.5; P = 0.09) and under-16s (IRR, 1.7; P = 0.03) had higher concussion incidence rates than the under-18 age group. The incidence was higher in the third (IRR, 2.1; P = 0.04) and fourth (IRR, 2.5; P = 0.01) quarters of matches compared with the first quarter. Sixty-two percent of concussions occurred in the tackle situation. The tackler had a 4-fold greater concussion rate (IRR, 4.3; P < 0.001) compared with the ball carrier. The hooker and loose forwards had higher incidence rates than several other player positions (P < 0.05). CONCLUSIONS: The reported concussion incidence falls within the broad range previously reported in youth rugby. The evidence highlighted in this study may contribute to targeted concussion prevention strategies and provide a baseline against which the effectiveness of future interventions can be measured.

Genetics of Musculoskeletal Exercise-Related Phenotypes.

Genetic factors have been shown to associate with various exercise-related phenotypes, including exercise performance, adaptation to training and sports injuries. The genes implicated in the pathogenesis of musculoskeletal soft-tissue injuries all code for either structural components or regulatory components of the extracellular matrix. It has been hypothesized that these genetic associations with injuries are due to genetically regulated changes in mechanical properties of musculoskeletal soft tissue. Thus, the objective of this review is to highlight the research which has advanced our understanding of how genetic variation within these structural genes affects the properties of our connective tissue. The genetics of various exercise-related phenotypes, such as range of motion, endurance performance and exercise-associated muscle cramps, are reviewed. Lastly, a model is presented where genetic variations within a collagen-encoding gene result in a continuum of phenotype ranging from a normal tissue to a seriously deleterious or lethal disorder.