Browsing by Author "Collins, Malcolm"

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    The association of the AVPR2 gene with serum sodium and water imbalances during an Ironman Triathlon
    (2007) Ah Kun, Maresa; Collins, Malcolm
    It is well documented that participation in ultra-endurance events such as the Ironman Triathlon, can be associated with the development of post-race water and sodium imbalances in athletes. Variants within genes that encode for proteins that regulate thirst have been shown to be associated with weight changes during participation in an Ironman Triathlon. Recent evidence of mutations within the arginine vasopressin 2 receptor (AVPR2) gene, which encodes a constitutively active receptor in the collecting tubules of the kidney, resulted in increased water reabsorption and hyponatraemia in two unrelated male infants. This suggests that serum imbalances and hydration status in individuals participating in an endurance event may also be, in part, controlled by variants withink the AVPR2 gene. The aim of this study was to investigate whether polymorphisms within the AVPR2 gene are associated with exercise-associated serum sodium and/or water imbalances in triathletes who particpated in the 2006 South African Ironman Triathlon.
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    Characterisation of the 3'-UTR of the COL5A1 gene: implication for musculoskeletal soft tissue injuries
    (2015) Laguette, Mary-Jessica Nancy; Collins, Malcolm; Prince, Sharon
    COL5A1 encodes the α1 chain of type V collagen, a minor fibrillar collagen that is an important regulator of collagen fibril assembly. A polymorphism (rs12722, C/T) within the 3'-untranslated region (UTR) of COL5A1 is associated with chronic Achilles tendinopathy (TEN) and other soft tissue injuries as well as exercise-related phenotypes. These phenotypes are directly or indirectly associated with the mechanical properties of musculoskeletal soft tissue. It has therefore been hypothesised that variants in the COL5A1 gene, specifically the 3'-UTR, regulate synthesis of the α1(V) chain and type V collagen production. Type V collagen levels in turn regulate fibril architecture and structure and, thereby, mechanical properties of musculoskeletal soft tissues. Although the 3'-UTR of many eukaryotic genes have been shown to play an important regulatory role, the function of the COL5A1 3'-UTR is currently unknown. Aim. The primary aim of this thesis was therefore to determine whether the COL5A1 3'-UTR was functional and to identify functional differences between the COL5A1 3'-UTR cloned from participants with TEN and healthy asymptomatic control individuals. The secondary aim was to start mapping the functional regions within the 3'-UTR, focusing on regions which are potentially responsible for contributing to the tendinopathic phenotype.
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    A comparison of two treatment protocols in the management of exercise-associated postural hypotension (EAPH) : a randomised clinical trial
    (2007) Anley, Cameron; Schwellnus, Martin; Noakes, Tim; Collins, Malcolm
    The aim of this study was to compare which of the two commonly used treatment protocols for Exercise Associated Postural Hypotension (EAPH) (Trendelenburg with oral fluids ad libitum or intravenous fluids) result in quicker recovery and earlier discharge from the medical facility.
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    Concussion-Associated Polygenic Profiles of Elite Male Rugby Athletes
    (2022-05-04) Antrobus, Mark R; Brazier, Jon; Callus, Peter C; Herbert, Adam J; Stebbings, Georgina K; Khanal, Praval; Day, Stephen H; Kilduff, Liam P; Bennett, Mark A; Erskine, Robert M; Raleigh, Stuart M; Collins, Malcolm; Pitsiladis, Yannis P; Heffernan, Shane M; Williams, Alun G
    Due to the high-velocity collision-based nature of elite rugby league and union, the risk of sustaining a concussion is high. Occurrence of and outcomes following a concussion are probably affected by the interaction of multiple genes in a polygenic manner. This study investigated whether suspected concussion-associated polygenic profiles of elite rugby athletes differed from non-athletes and between rugby union forwards and backs. We hypothesised that a total genotype score (TGS) using eight concussion-associated polymorphisms would be higher in elite rugby athletes than non-athletes, indicating selection for protection against incurring or suffering prolonged effects of, concussion in the relatively high-risk environment of competitive rugby. In addition, multifactor dimensionality reduction was used to identify genetic interactions. Contrary to our hypothesis, TGS did not differ between elite rugby athletes and non-athletes (p ≥ 0.065), nor between rugby union forwards and backs (p = 0.668). Accordingly, the TGS could not discriminate between elite rugby athletes and non-athletes (AUC ~0.5), suggesting that, for the eight polymorphisms investigated, elite rugby athletes do not have a more ‘preferable’ concussion-associated polygenic profile than non-athletes. However, the COMT (rs4680) and MAPT (rs10445337) GC allele combination was more common in rugby athletes (31.7%; p < 0.001) and rugby union athletes (31.8%; p < 0.001) than non-athletes (24.5%). Our results thus suggest a genetic interaction between COMT (rs4680) and MAPT (rs10445337) assists rugby athletes in achieving elite status. These findings need exploration vis-à-vis sport-related concussion injury data and could have implications for the management of inter-individual differences in concussion risk.
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    Dietary fat modulates the relationship between polymorphisms in the TNFA and IL-6 genes, and obesity and serum lipid concentrations in black and white South Afican women
    (2013) Joffe, Yael; Goedecke, Julia; Collins, Malcolm; Van der Merwe, Lize
    The primary aim of the thesis was to investigate associations between TNFA (TNFA-308 G>A and -238 G>A) and IL-6 (-174 G>C, IVS3+281 G>T, IVS4+869 A>G) sequence variants and obesity and serum lipid concentrations in black and white SA women. This included identifying sequence variants in the IL-6 gene with a reported high heterozygosity in both the white and black SA populations (rs1554606 and sr2069845). Dietary intake data of adequate reporters was then included in the analysis to investigate whether dietary fatty acid intake modulated the interactions between the TNFA and IL-6 SNPs (TNFA -308 G>A and -238 G>A & IL-6 -174 G>C, IVS3+281 G>T, IVS4+869 A>G) and obesity, measures of adiposity and serum lipid concentrations, and whether interactions identified differed between black and white women.
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    The effect of chronic exposure to endurance exercise on the skeletal muscle of distance runners
    (2007) Rae, Dale Elizabeth; Collins, Malcolm; Lambert, Mike
    It is likely that masters runners may experience an intolerance to exercise primarily due to the age-related changes in their bodies, and specifically of those systems and organs most utilised during running. A more disturbing phenomenon, however, is that of younger runners becoming exercise intolerant. One study described exercise intolerance in athletes who were only 40 +/- 10 years old. The muscle of these athletes had greater levels of markers of structural pathology and showed evidence of having undergone more regeneration compared to age- and mileage-matched apparently healthy athletes. The authors attributed their intolerance to exercise to their large volumes of endurance training and racing which compromised their skeletal muscle. Therefore, the objective of this thesis was to examine the effects of chronic exposure to endurance running on the athlete, with particular emphasis on skeletal muscle.
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    Effects of elevated plasma adrenaline levels on substrate metabolism, effort perception and muscle activation during low-to-moderate intensity exercise
    (2005) West, Sacha J; Goedecke, Julia H; Van Niekerk, Lizl; Collins, Malcolm; St Clair Gibson, Alan; MacDonald, Ian A; Noakes, Timothy D; Lambert, Estelle V
    The aim of this study was to differentiate the role of raised plasma adrenaline (Adr) concentrations from sympathoadrenal activation associated with moderate-intensity exercise, on muscle activation, cardiopulmonary responses, fuel metabolism, and ratings of perceived exertion (RPE) during low-intensity exercise. Two groups of subjects (MOD, n=6; LOW, n=7) cycled on two occasions for 90 min. MOD cycled at 68% VO2max with saline infusion, and at 34% VO2max with Adr infusion. LOW cycled twice at 34% VO2max, with either Adr or saline infusion. Infusions (0.015 g Adr/kg/min) started at 15 min and increased plasma [Adr] somewhat higher than during exercise at 68% VO2max (~1.9 vs. 1.4 nM, at 75 min). Mean plasma glucose and lactate concentrations during LOW were significantly higher with Adr than saline infusion (5.1±0.6 vs. 4.4±0.3 mmol/l, P<0.01 and 2.1±0.8 vs. 1.3±0.5 mmol/l, P<0.01, respectively). Elevated [Adr], without increased exercise intensity, did not alter glycogenolysis. There were also no effects of Adr infusion at 34% VO2max on heart rate, oxygen consumption, [FFA], respiratory exchange ratio, intramuscular triglyceride utilization, muscle activation or RPE. In conclusion, elevated [Adr] similar to those found during moderate-intensity exercise increased plasma glucose and lactate availability, but did not alter intramuscular fuel utilization, effort perception or muscle activation.
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    Endurance performance : the integrative physiology of resisting fatigue
    (2004) Harley, Yolande Xanthe Rocille; Gibson, Alan St Clair; Collins, Malcolm
    Includes bibliographical references.
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    Exercise-associated muscle cramping (EAMC) in Ironman triathletes
    (2006) Drew, Nichola; Schwellnus, Martin; Collins, Malcolm
    Exercise-associated muscle cramping (EAMC) is a common condition of spontaneous, painful skeletal muscle spasms that occur in exercising muscles during exercise or in the immediate post-exercise period. There is a high prevalence in endurance athletes, including ultra-distance triathletes. The exact cause for this condition has not been defined but various hypotheses have been proposed. Over the last decade the ""fatigue hypothesis"" has received most of the support in the scientific literature. Evidence from animal experiments, clinical studies on endurance athletes and situational information, suggest that neuromuscular fatigue may precede the increased neuromuscular excitability leading to EAMC. The objective of this research study was to identify factors associated with EAMC in endurance triathletes in an attempt to further elucidate the aetiology. Triathletes competing in the 2006 South African lronman triathlon were recruited as subjects in a prospective cohort study. A total of 44 triathletes made up the cramping group and 166 the non-cramping group. A detailed questionnaire, including information on training, personal best performances and a cramping history was completed by both groups of triathletes. Full clinical data was also collected from both groups. This included pre-and post race body weights, and pre- and post-race serum electrolyte concentrations. The main findings of the study were that the two independent risk factors for EAMC in these triathletes were a faster overall race time (and cycling time), and a past history of cramping (in the last 10 races). Results showed that EAMC was correlated with faster overall and cycle section times. The athletes who had experienced cramps in this event not only achieved taster race times but also predicted faster times, despite similarly matched preparation and performance histories as those who did not cramp. A higher intensity of racing would thus be required by these athletes, predisposing them to premature fatigue. The results thus agree with the ""fatigue hypothesis"" as an aetiological mechanism for EAMC. This study also showed no correlation between EAMC and changes in hydration status or changes in serum electrolyte concentration. This study thus adds to the evidence against disturbances in hydration and electrolyte balance as causes for cramping in exercise and further focuses attention on neuromuscular fatigue as a possible primary factor.
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    Exercise-induced protection against insulin resistance and type 11 diabetes : the role of calcium
    (2008) Smith, James Antony Harris; Ojuka, Edward; Collins, Malcolm
    Regular exercise protects individuals against developing insulin resistance and type II diabetes. This effect of exercise does not appear to be due to an improvement in the insulin signalling pathway but instead due to an increase in the content of the insulin-regulatable glucose transporter (GLUT4) in skeletal muscle (84). Understanding the mechanisms by which exercise increases GLUT4 levels in skeletal muscle may reveal targets for pharmaceuticals to treat insulin resistance and type II diabetes. Although in vitro binding assays have shown that GLUT4 expression during exercise is mediated by the binding of myocyte enhancer factor-2A (MEF2A) to its cis-element on the Glut4 promoter (122), this has not been demonstrated in vivo. Moreover, the mechanisms by which exercise increases MEF2A binding to the Glut4 promoter have not been fully characterised.
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    Extracellular matrix gene sequence variant analyses and Achilles tendinopathy
    (2013) Saunders, Colleen Jayne; September, Alison; Schwellnus, Martin; Collins, Malcolm
    The primary aim of this thesis was to identify additional genetic elements predisposing individuals to risk of AT using a candidate gene, case-control genetic association approach, and to propose the biological mechanisms underlying this genetic risk. Candidate genes (COMP, THBS2, COL27A1, TNC, COL3A1, COL5A2 and COL5A3) were selected based on their chromosomal location and/or the biological function of their encoded proteins within the extracellular matrix (ECM) of the tendon.
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    Gastrointestinal tract (GIT) symptons in Ironman triathletes : a study relating GIT symptons to changes in splanchnic blood flow
    (2008) Wright, Helen; Schwellnus, Martin; Collins, Malcolm
    Gastrointestinal tract (GIT) symptoms commonly affect endurance athletes such as those competing in the Ironman Triathlon. Although a number of risk factors and the pathophysiological mechanisms for the development of GIT symptoms during exercise have been proposed, scientific evidence in support of these factors and mechanisms is limited. Altered blood flow to the GIT during exercise have been suggested as a possible mechanism for the pathophysiology of GIT symptoms. However, changes in blood flow in the superioir mesentric artery (SMA) and the coeliac artery in athletes presenting with GIT symptoms during exercise have not previously been investigated.
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    Genetic factors associated with performance and exercise-associated weight loss in Ironman triathletes
    (2012) De Milander, Liesl; Collins, Malcolm
    The aim of this thesis was to investigate candidate genes, mainly within the CNS, that may contribute to the variation in physiological responses (body weight changes) and athletic ability between athletes during participation in a 226 km Ironman triathlon. A genetic association approach was used in case-control studies to identify specific sequence variants within selected candidate genes. These candidate genes (IL-6, 5-HTT and MAO-A) were selected based on the biological function of their encoded proteins, which have been implicated in peripheral and central fatigue models. Candidate genes (5-HTT and AVPR2) that encode for proteins that play key roles in the neuro-endocrine control of total body water homeostasis were also investigated in this thesis.
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    Genetic risk factors for anterior cruciate ligament ruptures
    (2009) Posthumus, Michael; Collins, Malcolm; Schwellnus, Martin
    The primary aim of this thesis was to identify candidate genes that may be associated with ACL ruptures, and then use a genetic association approach following a case-control study design to identify specific sequence variants (single nucleotide polymorphisms, SNPs) within these candidate genes which may predispose individuals to ACL ruptures. Candidate genes (COL1A1, COL5A1 and COL12A1) were selected based on the biological function of their encoded proteins (type I, type V and type XII collagen respectively) within the basic structural and functional unit of ligaments, namely the collagen microfibril.
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    Genetic risk factors for carpal tunnel syndrome
    (2014) Burger, Marilize Cornelle; Collins, Malcolm
    Carpal tunnel syndrome (CTS) is a common occupational injury that is caused by an increase in pressure within the carpal tunnel structure which, in turn, causes compression of the median nerve. Although several factors are believed to be associated with increased risk of CTS, the direct causes of this injury remain unknown and it is generally accepted that CTS, with the exception of acutely caused CTS, is a multifactorial condition. Although it is generally accepted that an increase in pressure within the carpal tunnel structure, which contains nine flexor tendons, causes compression of the median nerve, the involvement of these tendons and other connective tissue structures in the aetiology of CTS cannot be excluded. In support of this, pathology of these connective structures have been proposed as being comorbid conditions or a precursor of CTS, cause CTS and/or can lead to an increase in carpal tunnel pressure. Several studies have suggested that specific non-occupational risk factors, such as anatomical, systemic and chronic factors as well as mostly repetition- and force-related occupational risk factors are associated with CTS. Although genetic influences in the aetiology of CTS have been proposed, this area has received little attention. Common DNA sequence variants on the other hand have previously been reported to associate with common exercise-associated tendon, such as chronic Achilles tendinopathy, and ligament injuries. The aim of this thesis was to determine whether common DNA sequence variants within several genes that have been associated or implicated in the aetiology of exercise-related musculoskeletal soft tissue injuries, are associated with altered risk of CTS by using a genetic association case-control study approach.
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    Genetic risk factors for overuse and acute musculoskeletal injuries
    (2024) Hill, Lee-Devlin; Collins, Malcolm; Posthumus, Michael
    Both acute and chronic tendon and ligament injuries are multifactorial that are the result of a combination of a poorly understood complex interaction of several intrinsic and extrinsic risk factors. There is a growing body of evidence suggesting that inherited genetic elements may predispose an individual to injury risk and should therefore be considered as important intrinsic risk factors. Previous studies have investigated the association several collagen gene (COL1A1, COL5A1, COL6A1, COL11A1, COL11A2 and COL12A1) variants with chronic lower limb tendinopathies, such as Achilles tendinopathy, and other exercise-associated phenotypes involving the musculoskeletal system. These genes encode for important structural components of both tendons and ligaments and have been proposed to influence the inter-individual variation in the biomechanical properties of these tissues. The association of these collagen gene variants with rotator cuff tendinopathy (RCT), more specifically supraspinatus tendinopathy (SST), has not been extensively investigated. Except for COL1A1 variants, the association of the remaining collagen gene variants with an acute injury, such as anterior cruciate ligament (ACL) ruptures, has also not been extensively investigated. AIMS Therefore, the primary aim of this thesis was to investigate the association of the COL1A1 rs1800012 (G/T), COL5A1 rs12722 (T/C), COL5A1 rs10628678 (AGGG/-), COL6A1 rs35796750 (T/C), COL11A1 rs3753841 (T/C), COL11A1 rs1676486 (C/T), COL11A2 rs1799907 (A/T) and COL12A1 rs970547 (G/A) gene variants with RCT in a South African cohort of swimmers (Chapter 4), as well as ACL rupture in a combined cohort of European ancestry (Swedish, South African, Polish and Australian) (Chapter 5) and a South African Mixed Ancestry cohort (Chapter 6) using a case-control genetic association study approach. A secondary aim of the thesis was to investigate hypothesis-driven collagen gene-gene interactions between the investigated variants in modulating the risk of injury in the different RCT (Chapter 4) and ACL (Chapters 5 and 6) cohorts. Finally, a systematic review of the risk factors associated with RCT in swimmers was also included in this thesis (Chapter 3). METHODS For chapter 4, 103 (49 females, 54 males) swimmers with clinically diagnosed rotator cuff tendinopathy (RCT group) were recruited of the 103 participants in the RCT group, 84.5% (n=87) were diagnosed with a supraspinatus tendinopathy (SST) and were analysed separately as a sub-group. In addition, 101 (55 females,46 males) apparently healthy swimmers with no previous history of shoulder pathology (including RCT, trauma, bursitis, or adhesive capsulitis) (CON group) were recruited. All participants were unrelated, of self-reported European ancestry and recruited between 2013 and 2016. For Chapter 5, 195 physically active and unrelated participants of self-reported European ancestry were recruited between 2011 and 2013 from the University Hospital in Umeå and orthopaedic clinics in Luleå, Sweden. These participants within this cohort comprised of 79 individuals who had clinically diagnosed ACL injuries with a non-contact mechanism of rupture (NON group) and 116 apparently healthy, asymptomatic individuals with no history of ACL injuries (CON group). The Swedish cohort was included in a larger combined analysis consisting of 661 participants with ACL rupture and 378 uninjured controls from previously published cohorts of self-reported European ancestry from South Africa, Poland, and Australia. For chapter 6, 209 unrelated participants with self-reported mixed ancestry participants were included in this study. The participants were previously recruited between January 2012 and May 2016 from Groote Schuur Hospital, Victoria Hospital, and the Sports Science Orthopaedic Clinic within the Cape Town, South Africa. Ninety-four participants (77 males and 17 females) were included in the ACL group, of which 51 had sustained their ACL rupture through a non contact mechanism of injury (NON sub-group. Furthermore, 100 (81 males and 19 females) apparently healthy, individuals with no history of ACL rupture or injury were recruited from gyms and local sports clubs within the Cape Town area of South Africa. All participants were genotyped for the following collagen gene polymorphisms: COL1A1 rs1800012 (G/T), COL5A1 rs12722 (T/C) and rs10628678 (AGGG/-), COL6A1 rs35796750 (T/C), COL11A1 rs3753841 (T/C) and rs1676486 (C/T), COL11A2 rs1799907 (A/T) and COL12A1 rs970547 (G/A). RESULTS As presented in a systematic review of non-genetic risk factors (Chapter 3), only four risk factors for shoulder injuries were determined to be of moderate certainty, with the remaining 25 risk factors being appraised as low certainty. Moderate level of certainty was determined in (i) previous history of pain and injury, (ii) internal/external rotation range of motion, (iii) clinical joint laxity and instability and (iv) internal/external rotation strength. Although previously associated in some studies investigating other overuse musculoskeletal soft tissue injuries, none of the investigated collagen variants were independently associated with rotator cuff tendinopathy (RCT) or supraspinatus tendinopathy (SST) risk (Chapter 4). A novel finding of this thesis was that the C-A-(-) inferred haplotype constructed from COL11A1 rs3753841(T/C), COL11A2 rs1799907 (A/T) and COL5A1 rs10628678 (AGGG/-) was found to be significantly over-represented in the CON group (6.0 %) compared to the SST (0.4 %) groups (p=0.034). However, none of the inferred haplotypes constructed from (i) the two COL5A1 variants, (ii) the two COL11A1 variants, (iii) the three COL11A1 and COL11A2 variants, as well as all (iv) the COL11A1, COL11A2 and COL5A1 variants were associated with RCT or SST risk. Similarly inferred haplotypes constructed from (i) COL5A1 and COL6A1, (ii) COL5A1 and COL12A1, as well as (iii) COL6A1 and COL12A1 were also not associated with RCT or SST. The COL1A1 rs1800012 TT genotype was found to be significantly (p=0.027) under represented in the ACL (GG 68.0%, GT 30.9%, TT 1.1%) group of European ancestry during the combined analysis compared to the CON group (GG 67.0%, GT 29.0%, TT 4.0 %). A novel finding of this thesis was that this association was only observed in female (p = 0.045, OR = 0.00, CI 0.00 – 0.71; ACL: GG 68.1%, GT 31.9%, TT 0.0%; CON: GG 68.3%, GT 27.0%, TT 4.8%) but not male (p =0.299; ACL: GG 68.0%, GT 39.5%, TT 1.5%; CON: GG 66.5%, GT 31.0%, TT 3.6%) ACL groups. Although independently associated with ACL rupture in European populations, the COL1A1 rs1800012 TT genotype was however not significantly associated with ACL rupture in the Mixed Ancestry cohort (ACL: 85.4% GG, 13.5% GT and 1.0% TT vs CON: 82.3% GG, 17.7% GT and 0.0% GG, p=0.204). An additional novel finding was that the COL12A1 rs970547 polymorphism was significantly associated with risk in a South African Mixed Ancestry ACL rupture cohort (NON: 34.9% AA, 44.2% GA and 20.9% GG vs CON: 34.4% AA, 60.2% AG and 5.4% GG, p=0.021). This variant was however not associated with ACL rupture in the European populations (ACL: AA 63.7%, GA 31.3%, GG 5.1%) compared to the combined CON group (CON: AA 60.4%, GA 35.3%, GG 4.3%, p=0.423). None of the other investigated collagen gene variants were independently associated with ACL rupture in the European or mixed ancestry cohorts. Within participants of European ancestry, the C-AGGG (31.2% ACL vs 20.6% CON, p=0.001) and T-(-) (14.4% ACL vs 5.7% CON, p=0.010) inferred haplotypes constructed from COL5A1 rs12722 (C/T) and rs10628678 (AGGG/-) were significantly over-represented in the ACL rupture group. On the other hand the T-AGGG inferred haplotype was significantly (p>0.001) over-represented in the CON group (50.5%) compared to the ACL group (36.6%). None of the COL5A1 inferred haplotypes were however significantly associated with ACL rupture in the South African mixed ancestry cohort. A further novel finding was a significant interaction between the COL6A1 rs35796750 and COL12A1 rs970547 variants, the T-A inferred haplotype was significantly (p=0.030) over represented in the ACL group (11.0%) compared to the CON group (7.1%) when the participants of European ancestry were analysed. The T-G inferred haplotype was significantly (p=0.010) over-represented in the male CON sub-group (33.7%) compared to the male ACL sub group (23.0%) in the participants of European ancestry. Within the South African mixed ancestry population, the C-G inferred haplotype constructed from the COL6A1 and COL12A1 variants was significantly (p=0.029) over-represented in the ACL group (37.2%) compared to the CON group (31.1%). This haplotype remained significantly (p=0.027) associated when only the participants with a non-contact mechanism of injury (34.3% NON sub-group) was analysed. Finally, the inferred T-A haplotype constructed from COL5A1 rs12722 and COL12A1 rs970547 was significantly (p=0.039) with ACL rupture (27.3% ACL vs 17.9% CON) in the combined European cohort associated with risk. CONCLUSION This thesis investigated collagen gene variants that have been previously associated with a number of injury phenotypes and other exercise-related conditions in three independent cohorts. Whilst only two variant were found to be independently associated with risk, several gene-gene interactions were observed, demonstrating the complex and multifactorial nature of the MSK injuries. These novel findings therefore draw attention to the possible important role that genetic factors in the aetiology of tendon and ligament pathologies. Furthermore, this thesis highlights the importance of conducting studies in non-European and genetically diverse populations.
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    The impact of body fat and its distribution on risk factors for cardiovascular disease in black South African women
    (2008) Jennings, Courtney L; Goedecke, Julia; Collins, Malcolm
    Obesity and obesity-related diseases are a large global problem in both developed and developing nations. In South Africa, a country currently undergoing epidemiological transition, the prevalence of obesity is high, particularly in urban black women. Early detection of overweight and obese individuals is essential for the management of obesity and its related co-morbidities; however, there is no ethnic-specific field measure of body fat percent validated for use in black South African women. Further, despite high levels of adiposity, these women have an atypical presentation of cardiovascular disease (CVD) risk factors, presenting with relatively low levels of visceral adipose tissue (VAT) and a favourable lipid profile compared to white women. As a result of this atypical presentation of CVD risk factors, a high prevalence of “healthy obesity” has been reported, although the determinants of this phenotype have not been systematically investigated. In addition, the applicability of commonly used diagnostic criteria for the determination of insulin resistance, which include enlarged waist circumference and dyslipidemia as components, has not been investigated in this population. Therefore, the overall aim of this thesis was to investigate the impact of body fat and its distribution on the presentation and identification of CVD risk factors in relatively young black South African women, prior to the onset of CVD. More specifically, the objectives were; i) to determine if near infrared interactance (NIR) is a valid field measure of body fat percent in South African women; ii) to determine the agreement between International Diabetes Federation (IDF) and National Cholesterol Education Program (Adult treatment panel III) (ATP III) metabolic syndrome criteria and the degree to which these criteria can predict insulin resistance, and explore the extent to which these phenomena can be explained by body fat and its distribution; iii) to identify determinants of the “metabolically healthy obese” (MHO) and “metabolically obese normal weight” (MONW) phenotypes; and iv) to complete a preliminary investigation of the association between polymorphisms within genes that encode for proteins involved in tissue-specific glucocorticoid metabolism and obesity, body fat distribution and CVD risk factors in black South African women. As obesity is associated with increased risk of cardiovascular disease, accurate quantification of body fatness is particularly important in health risk appraisal. However, in developing countries, “gold standard” measures of body fat percent such as underwater weighing and dual energy x-ray absorptiometry (DXA) are not always practical, as access to facilities and resources are limited. Therefore, a valid field measure of body fat percent is needed for the purpose of health risk appraisal. NIR is a potentially useful field measure of body fat percent that is currently used in South Africa for this purpose. However, NIR cannot be used with confidence in South Africa until it has been validated in different ethnic populations. Therefore, the first study in this thesis examined the validity of singlesite NIR (Futrex-6100 A/ZL) as a measure of body fat percent compared to the criterion method of DXA in black and white South African women.
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    Intrinsic and extrinsic factors associated with change in range of motion (ROM) after a single stretch session and repeated loading following an endurance run
    (2011) Miller, Caron-Jayne; Collins, Malcolm; Schwellnus, Martin
    Static stretching is commonly performed by athletes and clinicians on the assumption that it increases joint range of motion (ROM). However, observations from our laboratory indicate that there is an apparent inter-individual variance in the change in ROM in response to static stretching. Furthermore, prolonged repetitive loading has also been shown to affect ROM of a joint or series of joints. In particular, runners have a significantly decreased hamstring ROM. The aim of this study was to investigate the factors which are associated with a change in ROM in response to 1) a static stretch session and 2) prolonged repetitive loading. The findings showed that there is a variable response in the change in ROM following both a SSS intervention and in response to participation in a 42.2 or 56 km road race. More specifically, about 10% of the participants had a reduction in ROM after the SSS while the majority of participants had a reduced ROM after completing the marathon or ultra marathon.
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    Intrinsic and extrinsic factors associated with range of motion (ROM) with an emphasis on a novel genetic factor
    (2010) Brown, James Craig; Collins, Malcolm; Schwellnus, Martin
    Introduction: Although there are numerous health benefits associated with participating in regular physical activity, there is also an increased risk of sustaining injuries, in particular musculoskeletal soft tissue injuries. Both an increased and decreased joint range of motion (ROM) has been reported as one of the intrinsic risk factors for these injuries. Similarly to injury, the ROM trait has also been associated with various extrinsic and intrinsic factors. Extrinsic factors that are associated with ROM include level and type of sports participation and temperature. Intrinsic factors include age, gender, limb dominance, weight/BMI, height, prior injury, flexibility training, ethnicity and genotype. It has been reported that ROM is a largely (47-70%) heritable trait in both pathological and apparently healthy populations. Mutations within the COL5A1 gene cause classic Ehlers-Danlos Syndrome (EDS) which present with, among other clinical signs, generalised joint hypermobility. Furthermore, a COL5A1 gene sequence variant, the BstUI Restriction Fragment Length Polymorphism (RFLP), has previously been shown to be associated with ROM measurements in a cohort containing individuals with a history of Achilles tendon injuries. Objectives: The aim of this study was, therefore, to investigate the association between the COL5A1 BstUI (C/T) and DpnII (C/T) RFLPs, as well as non-genetic intrinsic and extrinsic factors, and ROM measurements in an apparently healthy and physically active population. 15 Methods: The sit and reach (SR), passive straight leg raise (SLR) and shoulder internal (ShIR) and external rotation (ShER) assessments were performed on 325 (204 males, 121 females) white, apparently healthy and physically active subjects. Subjects were genotyped for the BstUI (SNP rs12722) and DpnII (SNP rs13946) RFLPs within the 3-untranslated region (UTR) of the COL5A1 gene. Level and type of sport participation, age, gender, limb dominance, height, weight, BMI, waist circumference, prior injury and flexibility training were also recorded to investigate possible associations with ROM. Results: There was a significant interaction between age and COL5A1 BstUI genotype with SR ROM. Subjects with a CC genotype were 'protected' against the commonly reported age-related decline in SR ROM. This divergence in response to aging resulted in a significant difference in the mean SR ROM between the BstUI RFLP genotype groups of the 'old' ('¥35 years) (TT=225 ± 96 mm, TC=245 ± 100 mm, CC=321 ± 108 mm, N=96, p=0.017), but not the 'young' (<35 years) (N=197, p=0.626) subjects. While the DpnII RFLP displayed a similar pattern of divergence in SR ROM with aging, this interaction was not significant. Nevertheless, the SR means were significantly different between DpnII genotypes in the 'old' group when the TT and TC genotypes (T allele) were combined and compared against the CC genotype (T allele=244 ± 98 mm, CC genotype=332 ± 15 mm, N=93, p=0.032). Furthermore, flexibility training (stretching) was associated with increased ROM only in the BstUI TT genotype, suggesting a genotype-specific response. Of all the intrinsic and extrinsic factors 16 investigated in this cohort, only gender and genotype (either BstUI or DpnII RFLPs) were shown to contribute to SR ROM variance through multivariate analysis. Some inconsistent associations with intrinsic and extrinsic factors were observed with the SLR and shoulder ROM assessments, although small sample size and poor reliability of these measures made the results difficult to interpret with confidence. Conclusion: The significant interaction of COL5A1 BstUI RFLP genotype with age explains the differences in SR ROM measurements observed in older, but not younger, apparently healthy and physically active individuals. A similar, non-significant pattern in the DpnII RFLP resulted in significantly different SR ROM for the T allele in comparison to the CC genotype. Besides genotype, gender also an contributed significantly to SR ROM variance in the 'old' cohort. Genetic sequence variants, in conjunction with commonly listed non-genetic intrinsic and extrinsic factors, need to be considered in order to understand the observed variance in ROM in apparently healthy and physically active populations. Keywords: COL5A1 genotype, range of motion (ROM), apparently healthy and physically active population, intrinsic and extrinsic factors, age, flexibility training.
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    An investigation of DNA sequence variants in genes that regulate collagen fibrillogenesis and predisposition to musculoskeletal soft tissue injuries
    (2013) Hay, Melanie; Collins, Malcolm; Posthumus, Mike; September, Alison
    The aim of this dissertation was to use a case-control genetic study to investigate the association of polymorphisms within the COL5A1, MIR608, COL11A1 and COL11A2, genes with AT and/or ACL injuries in Caucasian populations. These aims were explored in three studies: i) Determine whether the COL5A1 rs71746744 (-/AGGG) and rs1134170 (A/T) polymorphisms and the MIR608 rs4919510 (C/G) polymorphism are associated with ACL rupture risk (Chapter 2). ii) Determine whether the COL11A1 rs3753841 (T/C) and rs1676486 (C/T) polymorphisms and the COL11A2 rs1799907 (A/T) polymorphism are associated with ACL rupture risk. A secondary aim was to determine whether the COL11A1 and COL11A2 polymorphisms interact with COL5A1 rs71746744 (-/AGGG) to modulate ACL rupture risk (Chapter 3). iii) Determine whether the COL11A1 rs3753841 (T/C) and rs1676486 (C/T) and COL11A2 rs1799907 (A/T) polymorphisms are associated with AT risk, and investigate whether these polymorphisms interact with each other, or with the COL5A1 rs71746744 (-/AGGG) polymorphism to modulate the risk of developing AT (Chapter 4).