1. bookVolume 62 (2018): Issue 1 (June 2018)
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1899-7562
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13 Jan 2009
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Interactions Between COL5A1 Gene and Risk of the Anterior Cruciate Ligament Rupture

Journal Details
License
Format
Journal
eISSN
1899-7562
First Published
13 Jan 2009
Publication timeframe
5 times per year
Languages
English
Introduction

The COL5A1 gene, localized on chromosome 9q34.3, encodes the alpha-1(V) chain of type V collagen. This minor fibrillar collagen plays acrucial role in the regulation of the size and configuration of other abundant fibrillar collagens supporting many tissues in the body, such as tendons, ligaments, and muscles (Birk at al., 1990).

It has been shown that mutation in the COL5A1 gene results in a 50% reduction of type V collagen and leads to poorly organized fibrils, decreased tensile strength, and reduced stiffness of connective tissue (Wenstrup et al., 2006). In addition, mutations within COL5A1 were implicated in Ehlers Danlos syndrome (Malfait et al., 2010; Myllyharju and Kivirikko, 2001), a condition characterized by joint hypermobility. The BstUI RFLP (rs12722) is a common C to T single nucleotide polymorphism (SNP) within the COL5A1 3′ untranslated region which may alter COL5A1 messenger RNA (mRNA) stability (Laguette et al., 2011). Previous studies identified the BstUI restriction fragment length polymorphism (RFLP) to be associated with chronic Achilles tendinopathy (Mokone et al., 2006; September et al., 2009), anterior cruciate ligament ruptures (O’Connell et al., 2015; Posthumus et al., 2009; Petr et al., 2014), carpal tunnel syndrome (Burger et al., 2015) and properties of the knee ligament (Kubo et al., 2013). In addition, this SNP was also associated with joint flexibility (Brown et al., 2011), joint range of motion (ROM) (Collins et al., 2009) and endurance running performance (Brown et al., 2011; Collins and Posthumus, 2011). It was hypothesized that individuals with the rs12722 TT genotype have increased type V collagen production and thus favorably altered mechanical properties of tendons, which potentially enhances endurance running ability (Collins et al., 2011; Posthumus et al., 2011). Moreover, individuals with the COL5A1 T functional allele are reported to have an increased mRNA stability in vitro (Laguette et al., 2011). In these investigations, the TT genotype has been prominent with phenotypes of stiffer tendon and ligamentous mechanical properties (Laguette et al., 2011).

Mokone et al. (2006) reported a significant difference in the allele frequencies of the COL5A1 rs13946 DpnII RFLP between the Achilles tendon pathology group and control groups). However, research investigating a group of recreational skiers showed no significant differences in rs13946 (C/T) genotype frequency distributions between the ACL rupture and control groups (Posthumus et al., 2009; Stępień-Słodkowska et al., 2015).

The aim of this study was to investigate the rs12722 and rs13946 polymorphisms in the COL5A1 gene, individually and as haplotypes, with the risk of ACL ruptures in soccer players. We postulated that the COL5A1 rs12722 and rs13946 polymorphisms would be individually associated with ACL rupture risk and that an inferred haplotype of the two polymorphisms may provide more information into the potential role of COL5A1 in predisposing professional soccer players to higher risk of ACL rupture (O’Connell et al., 2015).

Methods

This study was approved by the Gdansk Medical University Ethics Committee, Poland (number KB 8/16) and written informed consent was obtained from each participant according to the declaration of Helsinki. A total of 134 professional male soccer players (age = 23.4 ± 3.1 years), with surgically diagnosed primary ACL ruptures who qualified for ligament reconstruction, were recruited for this study. All players had non-contact ACL ruptures. For the obvious reason that the soccer teams were homogenous in term of gender, we recruited only male subjects. All participants were soccer players playing in the Polish 1st division professional soccer league, with overall training time of 14–18 h per week (7–9 training sessions a week, 2 h each). Subjects were treated in the Galen Orthopaedics Clinic in Poland.

The control group consisted of 211 apparently healthy, male professional soccer players (age = 25.3 ± 3.4 years), without any self-reported history of ligament or tendon injury. Both the ACL rupture group and the healthy controls were from the same soccer teams, of the same ethnicity (all self-reported Polish, East-Europeans for ≥3 generations), and had a comparable level of exposure to risk of ACL injury (same volume and intensity of training as well as hours of match play).

We followed the STREGA recommendations for genotype-phenotype association studies (Little et al., 2009). An oral epithelium was collected from each participant using the DNA Swab (Copan, USA). Genomic DNA was extracted from the oral epithelial cells using a Gen Elute Mammalian Genomic DNA Mini prep Kit (Sigma, Germany) according to manufacturer’s recommendations. Allelic discrimination of the COL5A1 rs12722 and rs13946 polymorphic sites (BstUI RFLP C/T and DpnII RFLP C/T, respectively) was performed using catalogued TaqMan® SNP Genotyping Assays (Applied Biosystems, USA). All samples were genotyped on a Rotor-Genereal-time polymerase chain reaction (PCR) instrument (Corbett, Australia) with the following cycling conditions: an initial hold step at 95°C for 5 min, followed by 45 cycles of denaturation at 94°C for 15 s and anneal/extend at 60°C for 1 min. 47 positive (known genotypes) and negative controls (no DNA) were included on each PCR plate as quality control measures. Genotyping results were called by two independent, experienced investigators who were blinded to the participants’ data.

Statistical Analysis

The programming language and environment R (http://www.r-project.org) was used for all statistical analyses. Genotype and allele frequencies were compared between the cases and controls using χ2 or Fisher exact tests. Allelic-based odds ratios (OR) with 95% confidence intervals (95%CI) were calculated using logistic regression analysis. The genotypes between cases and controls were compared in three ways: first, in a general test of association in the 2-by-3 table of phenotype-by-genotype, then two different modes of inheritance of the minor allele were assumed: dominant, in which homozygotes and heterozygotes for the minor allele were pooled and compared to homozygotes for the major allele and recessive, in which homozygotes and heterozygotes for the major alleles were pooled and compared to homozygotes for the minor allele. Hardy–Weinberg equilibrium probabilities and linkage disequilibrium (LD) between the SNPs were also calculated. The haplo.stats package was used to infer haplotype frequencies and to test the association between inferred haplotypes and the risk of ACL rupture assuming three possible haplotype effects: additive, dominant and recessive. Hap.score is the statistical co ref or haplotypes reflecting the strength of association; the positive value of Hap.score indicates increased risk of ACL injury for a particular haplotype, while a negative value indicates reduced risk. For all tests, significance was set at p < 0.05.

Results

At baseline, male professional soccer players with surgically diagnosed primary ACL ruptures and the control group did not differ significantly according to age and the level of exposure to ACL injury. The genotype and allele frequencies for the COL5A1 rs12722 and COL5A1 rs13946 are shown in Table 1. The genotype distributions for both polymorphisms met Hardy-Weinberg expectations in both groups.

COL5A1 rs12722 C/T and rs13946 C/T allelic and genotypic frequency distributions in the anterior cruciate ligament rupture group (ACL rupture group) in comparison with the control group.

SNPCON (n=211)ACL (n=134)p
COL5A1 rs12722TT62 (29%)45 (34%)0.661
CT107 (51%)66 (49%)pD = 0.411
CC42 (20%)23 (17%)pR = 0.526
C allele191 (45%)112 (42%)0.371
HWE0.7290.888
COL5A1 rsl3946TT94 (45%)75 (56%)0.091
CT102 (48%)49 (37%)pD = 0.039
CC15 (7%)10 (7%)pR = 0.902
C allele132 (31%)69 (26%)0.119
HWE0.0710.610

pD and pR are two-sided Fisher’s exact test probabilities for dominant (CC+CT vs TT) and recessive (CC+CT vs TT) modes of inheritance of the minor allele (rs12722 and rs13946), respectively. HWE: hardy Weinberg exact tests of significance

There were no significant differences in the genotype or allele frequency distribution for either COL5A1 (rs12722) or COL5A1 (rs13946) polymorphisms between the control group and the ACL rupture group using the 2-by-3 general test of association (Table 1). Likewise, there were no significant differences in the genotype frequencies for the COL5A1 rs12722 polymorphisms, when dominant and recessive modes of inheritance were assumed. However, significant differences in the genotype frequency distribution were noted for the COL5A1 rs13946 polymorphisms when a dominant mode of inheritance was tested (p = 0.039) (Table 1).

Evaluation of the haplotype frequency distribution for COL5A1 rs12722-rs13946 showed significant differences between the control group and the study participants. There were three haplotypes, T-T, C-C and C-T with frequencies of 56%, 29% and 15%, respectively. Specifically the C-C haplotype was found to be overrepresented in the control group compared to the ACLR group (p = 0.038) (Table 2) when the dominant model was tested.

Analysis of the frequency distributions of the COL5A1 rs12722-rs13946 haplotype in the study group and the control group for the three genetic models - dominant, recessive and additive.

(Haplotype (rs12722-rs13946))Control (n=211)Study (n=134)Dominant model (global-stat = 4.35, p = 0.226)Recessive model (global-stat = 4.72, p = 0.193)Additive model (global-stat = 2.75, p = 0.253)
T-T55%58%0.63, p = 0.5250.82, p = 0.4110.90, p = 0.366
C-C31%26%-2.06, p = 0.0380.12, p = 0.901-1.60, p = 0.107
C-T14%1%0.32, p = 7441.90, p = 0.0570.76, p = 0.442

global-stat –association of all haplotypes of the trait; hap.score – measure individual haplotype association to the trait; Significant p-values are in bold (p<0.05).

Discussion

Recent genetic research has summarised the specific markers to be associated with increased risk for sports injuries (Collins et al., 2015; Rahim et al., 2016; September et al., 2016) and performance-related conditions (Cupeiro et al., 2010; Maffulli et al., 2013; Wang et al., 2013). Use of this genetic information can aid in the identification of the biological pathways underpinning injury risk and may, in future, support the development of tailored injury prevention programmes for athletes and the application of targeted therapeutic interventions (Cięszczyk et al., 2017).

In our study, we examined the association between both COL5A1 rs12722 C/T (BstUI RFLP) and the COL5A1 rs13946 C/T (DpnII) polymorphisms individually and as haplotypes with anterior cruciate ligament rupture risk in professional soccer players. Our findings identified no significant differences in the genotype (under general model of association) and allele frequency distributions of any of these two polymorphisms between the control group and the ACL rupture group. However, the carriers of the rs13946 C allele were underrepresented in the ACL injury group compared with controls. Considering the lack of association in the allele-based test, our results are consistent with those previously reported by Stępień-Słodkowska et al. (2015) in recreational skiers from Poland. Similarly, we identified the T-T haplotype (COL5A1 rs12722 C/T-rs13946 C/T) to be the most common (56%). The similarities in the frequency distributions between the two independent studies may be a result of both study groups originating from Poland. Further research in larger sample sizes and in independent populations is needed to investigate the role of the rs12722 and the rs13946 polymorphisms in ACL rupture risk.

Previously the rs12722 CC genotype was found to be associated with ACL tears in females in a Caucasian study group from South Africa (Posthumus et al., 2009). In addition, the rs12722 SNP was also associated with the development of bilateral quadriceps tendon rupture (Longo et al., 2010) and both the rs12722 and rs13946 SNPs were identified as genetic risk factors for tennis elbow (Altinisik et al., 2015)

In this study we found significant differences in the genotype frequencies for the COL5A1 rs13946 polymorphisms in dominant modes of inheritance, underrepresentation tendency of the C-T haplotype in the ACLR group compared to controls.

However, the authors do note that the sample size in both studies is a major limitation for such genetic association study. It is therefore recommended that the number of subjects be increased for a more comprehensive risk profiling analysis for ACLR susceptibility.

Several additional polymorphisms within COL5A1 have also been associated with exercise-related phenotypes and are good candidates for further investigation. The MIR608 rs4919510 CC genotype was significantly over-represented in tendinopathy participants compared to asymptomatic controls (Laguette et al., 2011). Interestingly, the rs4919510 SNP (on chromosome 10q24) was associated with the functional microRNA (miRNA) binding site for Hsa-miR-608 within the COL5A1 3′-UTR, thereby affecting COL5A1 mRNA stability in vitro. Hsa-miRNA-608 binds to a functional polymorphic cis-acting element within the COL5A1 3′-UTR (Abrahams et al., 2013; Laguette et al., 2011). Kirk et al. (2016) indicated that the COL5A1 rs1536482 (A/G) and rs12722 (C/T) may potentially influence quadriceps muscle-tendon stiffness, but not low-level contractile properties.

Conclusions

Our results suggest that variation in the COL5A1 gene may be one of the non-modifiable factors associated with the ACL injury in professional soccer players. The C-C rs12722-rs13946 haplotype provides a protective effect against the ACL tear.

Practical Implications

Although there are no immediate clinical implications, these findings help identify the main biological pathways contributing to injury susceptibility. In future, these genetic risk factors could be included in multifactorial risk models to assess one’s ACL rupture susceptibility. Moreover, this information could support the development of tailored injury prevention programmes and/or targeted therapeutic interventions.

Analysis of the frequency distributions of the COL5A1 rs12722-rs13946 haplotype in the study group and the control group for the three genetic models - dominant, recessive and additive.

(Haplotype (rs12722-rs13946))Control (n=211)Study (n=134)Dominant model (global-stat = 4.35, p = 0.226)Recessive model (global-stat = 4.72, p = 0.193)Additive model (global-stat = 2.75, p = 0.253)
T-T55%58%0.63, p = 0.5250.82, p = 0.4110.90, p = 0.366
C-C31%26%-2.06, p = 0.0380.12, p = 0.901-1.60, p = 0.107
C-T14%1%0.32, p = 7441.90, p = 0.0570.76, p = 0.442

COL5A1 rs12722 C/T and rs13946 C/T allelic and genotypic frequency distributions in the anterior cruciate ligament rupture group (ACL rupture group) in comparison with the control group.

SNPCON (n=211)ACL (n=134)p
COL5A1 rs12722TT62 (29%)45 (34%)0.661
CT107 (51%)66 (49%)pD = 0.411
CC42 (20%)23 (17%)pR = 0.526
C allele191 (45%)112 (42%)0.371
HWE0.7290.888
COL5A1 rsl3946TT94 (45%)75 (56%)0.091
CT102 (48%)49 (37%)pD = 0.039
CC15 (7%)10 (7%)pR = 0.902
C allele132 (31%)69 (26%)0.119
HWE0.0710.610

Abrahams Y, Laguette MJ, Prince S, Collins M. Polymorphisms within the COL5A1 3′-UTR that alters mRNA structure and the MIR608 gene are associated with Achilles tendinopathy. Ann Hum Genet,2013; 77(3): 204–21410.1111/ahg.1201323347277AbrahamsYLaguetteMJPrinceSCollinsMPolymorphisms within the COL5A1 3′-UTR that alters mRNA structure and the MIR608 gene are associated with Achilles tendinopathyAnn Hum Genet201377320421423347277Open DOISearch in Google Scholar

Altinisik J, Meric G, Erduran M, Ates O, Ulusal AE, Akseki D. The BstUI and DpnII Variants of the COL5A1 Gene Are Associated With Tennis Elbow. Am J Sports Med, 2015; 43(7): 1784-178910.1177/036354651557866125896984AltinisikJMericGErduranMAtesOUlusalAEAksekiDThe BstUI and DpnII Variants of the COL5A1 Gene Are Associated With Tennis ElbowAm J Sports Med20154371784178925896984Open DOISearch in Google Scholar

Birk DE, Fitch JM, Babiarz JP, Doane KJ, Linsenmayer TF. Collagen fibrillogenesis in vitro: interaction of types I and V collagen regulates fibril diameter. J Cell Sci, 1990; 95: 649–6572384532BirkDEFitchJMBabiarzJPDoaneKJLinsenmayerTFCollagen fibrillogenesis in vitro: interaction of types I and V collagen regulates fibril diameterJ Cell Sci19909564965710.1242/jcs.95.4.6492384532Search in Google Scholar

Brown J, Miller C-J, Posthumus M, Schwellnus MP, Collins M. The COL5A1 gene, ultra-marathon running performance and range of motion. Int. J. Sports Physiol, Perform, 2011; 6(4): 485-49610.1123/ijspp.6.4.485BrownJMillerC-JPosthumusMSchwellnusMPCollinsMThe COL5A1 gene, ultra-marathon running performance and range of motionInt. J. Sports Physiol, Perform20116448549621934170Open DOISearch in Google Scholar

Brown JC, Miller C-J, Schwellnus MP, Collins M. Range of motion measurements diverge with increasing age for COL5A1 genotypes. Scand. J. Med. Sci. Sports, 2011; 21(6): e266-722136205310.1111/j.1600-0838.2010.01271.xBrownJCMillerC-JSchwellnusMPCollinsMRange of motion measurements diverge with increasing age for COL5A1 genotypesScand. J. Med. Sci. Sports2011216e2667221362053Search in Google Scholar

Burger M, de Wet H, Collins M. The COL5A1 gene is associated with increased risk of carpal tunnel syndrome. J Clin Rheumatol, 2015; 34(4): 767–77410.1007/s10067-014-2727-7BurgerMde WetHCollinsMThe COL5A1 gene is associated with increased risk of carpal tunnel syndromeJ Clin Rheumatol201534476777424966028Open DOISearch in Google Scholar

Cięszczyk P, Willard K, Gronek P, Żmijewski P, Trybek G, Gronek J, Weber-Rajek M, Stasny P, Petr M, Lulińska-Kuklik E, Ficek K, Kemeryte-Riaubiene E, Maculewicz E, September S. Are genes encoding proteoglycans really associated with the risk of anterior cruciate ligament rupture? Biol Sport, 2017; 34:97-10328566802CięszczykPWillardKGronekPŻmijewskiPTrybekGGronekJWeber-RajekMStasnyPPetrMLulińska-KuklikEFicekKKemeryte-RiaubieneEMaculewiczESeptemberSAre genes encoding proteoglycans really associated with the risk of anterior cruciate ligament rupture?Biol Sport2017349710310.5114/biolsport.2017.64582542444828566802Search in Google Scholar

Collins M. Interactions between collagen gene variants and risk of anterior cruciate ligament rupture. Eur J Sport Sci, 2015; 15 (4): 341-3502507300210.1080/17461391.2014.936324CollinsMInteractions between collagen gene variants and risk of anterior cruciate ligament ruptureEur J Sport Sci201515434135025073002Search in Google Scholar

Collins M, Mokone GG, September AV, van der Merwe L, Schwellnus MP. The COL5A1 genotype is associated with range of motion measurements. Scand J MedSci Sports, 2009; 19(6): 803-81010.1111/j.1600-0838.2009.00915.xCollinsMMokoneGGSeptemberAVvan der MerweLSchwellnusMPThe COL5A1 genotype is associated with range of motion measurementsScand J MedSci Sports200919680381019422640Open DOISearch in Google Scholar

Collins M, Posthumus M. Type V collagen genotype and exercise-related phenotype relationships: a novel hypothesis. Exerc Sport Sci Rev, 2011; 39(4): 191–19821697718CollinsMPosthumusMType V collagen genotype and exercise-related phenotype relationships: a novel hypothesisExerc Sport Sci Rev201139419119810.1097/JES.0b013e318224e85321697718Search in Google Scholar

Collins M, September AV, Posthumus M. Biological variation in musculoskeletal injuries: current knowledge, future research and practical implications. Br J Sports Med, 2015: 49(23): 1497–150310.1136/bjsports-2015-09518026504180CollinsMSeptemberAVPosthumusMBiological variation in musculoskeletal injuries: current knowledge, future research and practical implicationsBr J Sports Med201549231497150326504180Open DOISearch in Google Scholar

Cupeiro R, Benito PJ, Maffulli N, Calderon FJ, Gonzalez-Lamuno D. MCT1 genetic polymorphism influence in high intensity circuit training: a pilot study. J Sci Med Sport, 2010; 13: 526–53010.1016/j.jsams.2009.07.00419850519CupeiroRBenitoPJMaffulliNCalderonFJGonzalez-LamunoDMCT1 genetic polymorphism influence in high intensity circuit training: a pilot studyJ Sci Med Sport20101352653019850519Open DOISearch in Google Scholar

Kirk EA, Moore CW, Chater-Diehl EJ, Singh SM, Rice CL. Human COL5A1 polymorphisms and quadriceps muscle-tendon mechanical stiffness in vivo. Exp Physiol, 2016; 101(12): 1581-159210.1113/EP08597427717059KirkEAMooreCWChater-DiehlEJSinghSMRiceCLHuman COL5A1 polymorphisms and quadriceps muscle-tendon mechanical stiffness in vivoExp Physiol2016101121581159227717059Open DOISearch in Google Scholar

Kubo K, Yata H, Tsunoda N. Effect of gene polymorphisms on the mechanical properties of human tendon structures. Springerplus, 2013; 25 (2): 343KuboKYataHTsunodaNEffect of gene polymorphisms on the mechanical properties of human tendon structuresSpringerplus201325234310.1186/2193-1801-2-343372852823961408Search in Google Scholar

Laguette MJ, Abrahams Y, Prince S, Collins M. Sequence variants within the 3′-UTR of the COL5A1 gene alters mRNA stability: implications for musculoskeletal soft tissue injuries. Matrix Biol, 2011; 30(5–6): 338–34510.1016/j.matbio.2011.05.00121609763LaguetteMJAbrahamsYPrinceSCollinsMSequence variants within the 3′-UTR of the COL5A1 gene alters mRNA stability: implications for musculoskeletal soft tissue injuriesMatrix Biol2011305-633834521609763Open DOISearch in Google Scholar

Little J, Higgins JP, Ioannidis JP, Moher D, Gagnon F, von Elm E, Khoury MJ, Cohen B, Davey-Smith G, Grimshaw J, Scheet P, Gwinn M, Williamson RE, Zou GY, Hutchings K, Johnson CY, Tait V, Wiens M, Golding J, van Duijn C, McLaughlin J, Paterson A, Wells G, Fortier I, Freedman M, Zecevic M, King R, Infante-Rivard C, Stewart A, Birkett N. STrengthening the REporting of Genetic Association studies (STREGA) - an extension of the STROBE statement. Eur J Clin Investig, 2009: 39(4): 247–26610.1111/j.1365-2362.2009.02125.xLittleJHigginsJPIoannidisJPMoherDGagnonFvon ElmEKhouryMJCohenBDavey-SmithGGrimshawJScheetPGwinnMWilliamsonREZouGYHutchingsKJohnsonCYTaitVWiensMGoldingJvan DuijnCMcLaughlinJPatersonAWellsGFortierIFreedmanMZecevicMKingRInfante-RivardCStewartABirkettNSTrengthening the REporting of Genetic Association studies (STREGA) - an extension of the STROBE statementEur J Clin Investig2009394247266273048219297801Open DOISearch in Google Scholar

Longo UG, Fazio V, Poeta ML, Rabitti C, Franceschi F, Maffulli N, Denaro V. Bilateral consecutive rupture of the quadriceps tendon in a man with BstUI polymorphism of the COL5A1 gene. Knee Surg Sports Traumatol Arthrosc, 2010; 18(4): 514–51810.1007/s00167-009-1002-yLongoUGFazioVPoetaMLRabittiCFranceschiFMaffulliNDenaroVBilateral consecutive rupture of the quadriceps tendon in a man with BstUI polymorphism of the COL5A1 geneKnee Surg Sports Traumatol Arthrosc201018451451819956930Open DOISearch in Google Scholar

Maffulli N, Margiotti K, Longo UG, Loppini M, Fazio VM, Denaro V. The genetics of sports injuries and athletic performance. Muscles Ligaments Tendons J, 2013; 3: 173–18924367777MaffulliNMargiottiKLongoUGLoppiniMFazioVMDenaroVThe genetics of sports injuries and athletic performanceMuscles Ligaments Tendons J2013317318910.32098/mltj.03.2013.09Search in Google Scholar

Malfait F, Wenstrup RJ, De Paepe A. Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type. Genet Med, 2010; 12(10): 597–6052084769710.1097/GIM.0b013e3181eed412MalfaitFWenstrupRJDe PaepeAClinical and genetic aspects of Ehlers-Danlos syndrome, classic typeGenet Med2010121059760520847697Search in Google Scholar

Mokone GG, Schwellnus MP, Noakes TD, Collins M. The COL5A1 gene and Achilles tendon pathology. Scand J Med Sci Sport, 2006; 16(1): 19–2610.1111/j.1600-0838.2005.00439.xMokoneGGSchwellnusMPNoakesTDCollinsMThe COL5A1 gene and Achilles tendon pathologyScand J Med Sci Sport2006161192616430677Open DOISearch in Google Scholar

Myllyharju J, Kivirikko KI. Collagens and collagen-related diseases. Ann Med, 2001; 33(1): 7–211131094210.3109/07853890109002055MyllyharjuJKivirikkoKICollagens and collagen-related diseasesAnn Med200133172111310942Search in Google Scholar

O’Connell K, Knight H, Ficek K, Leońska-Duniec A, Madejewska-Karlowska A, Sawczuk M, Stępień-Słodkowska M, O’Cuinneagain D, van der Merwe W, Posthumus M, Cięszczyk P, Collins M. Interactions between collagen gene variants and risk of anterior cruciate ligament rupture. Eur J Sport Sci, 2015; 15(4): 341-3502507300210.1080/17461391.2014.936324O’ConnellKKnightHFicekKLeońska-DuniecAMadejewska-KarlowskaASawczukMStępień-SłodkowskaMO’CuinneagainDvan der MerweWPosthumusMCięszczykPCollinsMInteractions between collagen gene variants and risk of anterior cruciate ligament ruptureEur J Sport Sci201515434135025073002Search in Google Scholar

Petr, M., Štastný, P., Pecha, O., Šteffl, M., Šeda, O., & Kohlíková, E. (2014). PPARA intron polymorphism associated with power performance in 30-s anaerobic Wingate Test. PloS one, 9(9): 107171.10.1371/journal.pone.0107171PetrM.ŠtastnýP.PechaO.ŠtefflM.ŠedaO.KohlíkováE.2014PPARA intron polymorphism associated with power performance in 30-s anaerobic Wingate TestPloS one99107171415781525198533Open DOISearch in Google Scholar

Posthumus M, Schwellnus MP, Collins M. The COL5A1 gene: a novel marker of endurance running performance. Med Sci Sports Exerc, 2011; 43(4): 584–58910.1249/MSS.0b013e3181f34f4d20798666PosthumusMSchwellnusMPCollinsMThe COL5A1 gene: a novel marker of endurance running performanceMed Sci Sports Exerc201143458458920798666Open DOISearch in Google Scholar

Posthumus M, September AV, O’Cuinneagain D, van der Merwe W, Schwellnus MP, Collins M. The COL5A1 gene is associated with increased risk of anterior cruciate ligament ruptures in female participants. Am J Sports Med, 2009; 37(11): 2234–22401965442710.1177/0363546509338266PosthumusMSeptemberAVO’CuinneagainDvan der MerweWSchwellnusMPCollinsMThe COL5A1 gene is associated with increased risk of anterior cruciate ligament ruptures in female participantsAm J Sports Med200937112234224019654427Search in Google Scholar

Rahim M, Collins M, September AV. Genes and musculoskeletal soft-tissue injuries. In M. Posthumus & M. Collins, eds. Medicine and Sport Science, Basel, Karger, 2016; 68–9127287078RahimMCollinsMSeptemberAVGenes and musculoskeletal soft-tissue injuriesPosthumusMCollinsM.Medicine and Sport ScienceBaselKarger2016689110.1159/00044524327287078Search in Google Scholar

September AV, Cook J, Handley CJ, van der Merwe L, Schwellnus MP, Collins M. Variants within the COL5A1 gene are associated with Achilles tendinopathy in two populations. Br J Sports Med, 2009; 43(5): 357–36510.1136/bjsm.2008.04879318443036SeptemberAVCookJHandleyCJvan der MerweLSchwellnusMPCollinsMVariants within the COL5A1 gene are associated with Achilles tendinopathy in two populationsBr J Sports Med200943535736518443036Open DOISearch in Google Scholar

September AV, Rahim M, Collins M. Towards an understanding of the genetics of tendinopathy. In P. W. Ackermann & D. A. Hart, eds. Advances in Experimental Medicine and Biology. Advances in Experimental Medicine and Biology, Cham: Springer International Publishing, 109–116; 2016SeptemberAVRahimMCollinsMTowards an understanding of the genetics of tendinopathyAckermannP.W.HartD. A.Advances in Experimental Medicine and Biology. Advances in Experimental Medicine and BiologyChamSpringer International Publishing109116201610.1007/978-3-319-33943-6_927535252Search in Google Scholar

Stępień-Słodkowska M, Ficek K, Kaczmarczyk M, Maciejewska-Karłowska A, Sawczuk M, Leońska-Duniec A, Stępiński M, Ziętek P, Król P, Chudecka M, Cięszczyk P. The Variants Within the COL5A1 Gene are Associated with Reduced Risk of Anterior Cruciate Ligament Injury in Skiers. J Hum Kinet, 2015; 7 (45): 103-111Stępień-SłodkowskaMFicekKKaczmarczykMMaciejewska-KarłowskaASawczukMLeońska-DuniecAStępińskiMZiętekPKrólPChudeckaMCięszczykPThe Variants Within the COL5A1 Gene are Associated with Reduced Risk of Anterior Cruciate Ligament Injury in SkiersJ Hum Kinet201574510311110.1515/hukin-2015-0011441582325964814Search in Google Scholar

Wang G, Padmanabhan S, Wolfarth B, Fuku N, Lucia A, Ahmetov II, Cieszczyk P, Collins M, Eynon N, Klissouras V, Williams A, Pitsiladis. Genomics of elite sporting performance: what little we know and necessary advances. Adv Genet, 2013; 84: 123–149WangGPadmanabhanSWolfarthBFukuNLuciaAAhmetovIICieszczykPCollinsMEynonNKlissourasVWilliamsAPitsiladis. Genomics of elite sporting performance: what little we know and necessary advancesAdv Genet20138412314910.1016/B978-0-12-407703-4.00004-924262098Search in Google Scholar

Wenstrup RJ, Florer JB, Davidson JM, Phillips CL, Pfeiffer BJ, Menezes DW, Chervoneva I, Birk DE. Murine model of the Ehlers-Danlos syndrome. col5a1 haploinsufficiency disrupts collagen fibril assembly at multiple stages. J BiolChem, 2006; 281(18): 12888–12895WenstrupRJFlorerJBDavidsonJMPhillipsCLPfeifferBJMenezesDWChervonevaIBirkDEMurine model of the Ehlers-Danlos syndrome. col5a1 haploinsufficiency disrupts collagen fibril assembly at multiple stagesJ BiolChem2006281181288812895Search in Google Scholar

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