Background/Objectives: Adenosine monophosphate deaminase deficiency has been implicated in impaired exercise capacity. We examined whether the AMPD1 C34T (rs17602729) genotype was associated with athlete status and performance in distance runners (DRs) and rugby union (RU) athletes. Methods: Participants included 621 elite male RU athletes, 666 elite/sub-elite male and female DRs, and 1029 male and female non-athletes (NA), all of European ancestry. Genotyping was performed using real-time PCR with TaqMan reagents. Genotype and allele frequencies were compared using χ2 tests, while performance data were analysed using Kruskal-Wallis H, Mann-Whitney U, one-way ANOVA, and t-tests, with Benjamini-Hochberg correction applied for multiple comparisons. Results: Genotype and allele frequencies did not differ between athletes and NA or between athlete groups. In all DRs, run times did not differ between genotypes, although participants with the CT genotype in the elite and elite male subgroups were up to 5% faster than CC and TT homozygotes. In RU, participants with the CC genotype played 13% longer per appearance than those with the CT genotype, while forwards and front five participants with the CC genotype played 13% and 26% longer per appearance than T-allele carriers, respectively. Front five T-allele carriers made 75% more clean breaks than the front five with the CC genotype despite playing for a shorter time, although this finding should be interpreted cautiously. Conclusions: In summary, while the AMPD1 C34T genotype was not associated with athlete status, the CC genotype was associated with greater RU playing time per appearance in forwards, and the CT genotype was associated with superior performance in elite DRs.

OBJECTIVES:Pain is the primary symptom of Achilles tendinopathy, with neovascularisation implicated in symptom development despite unclear mechanisms. Neovascularisation and pain are regulated by vascular endothelial growth factor A (VEGFA) and its receptor, KDR. Since VEGFA polymorphisms have previously been associated with Achilles tendinopathy, this study aimed to determine whether VEGFA (rs699947 C>A, rs2010963 G>C) and/or KDR (rs2071559 C>T, rs1870377 A>T) polymorphisms are associated with exercise-related pain at injury onset, multiple and/or bilateral injuries, as well as self-reported pain using multidimensional pain scales. DESIGN:Case-control and cross-sectional genetic association study. METHODS:One hundred and eighty-nine controls without any history of tendon injuries and 181 participants with Achilles tendinopathy were recruited, of which 71 and 91 reported multiple-bilateral and single-unilateral injuries respectively, and genotyped for KDR and VEGFA. Pain was assessed using the VISA-A, short-form McGill Pain and short-form Brief Pain Inventory questionnaires. RESULTS:The KDR C-T and T-A (rs2071559, rs1870377) inferred haplotypes were associated with decreased (cases: 32.8%, controls: 44.3%, p = 0.009) and increased (cases: 22.1%, controls: 12.1%, p = 0.007) risk of multiple-bilateral tendinopathy, respectively. The C-C-T and A-T-A VEGFA (rs699947) and KDR (rs2071559, rs1870377) allele combinations were also associated with decreased (cases: 13.1%, controls: 20.9%, p = 0.018) and increased (cases: 14.0%, controls: 6.2%, p = 0.001) risk of multiple-bilateral tendinopathy, respectively. There were no significant differences in pain scores between the genotype groups. CONCLUSIONS:KDR and VEGF genetic variants are associated with susceptibility to bilateral and/or multiple Achilles tendinopathy, supporting the potential role for angiogenesis signalling pathways in injury risk.

Background Anterior cruciate ligament (ACL) ruptures are common musculoskeletal injuries, influenced by extrinsic and intrinsic factors such as genetic variations and anthropometric traits. While these factors contribute to ACL rupture susceptibility, their interactions are underexplored. Objectives To investigate the relationship between HSPG2 variants and anthropometric traits in participants from an ACL study from Poland and Sweden. Hypothesis Genetic variability within HSPG2 loci along with height variability may collectively contribute to ACL rupture susceptibility. Sample and methods A genetic case-control association study was conducted with two cohorts from Poland and Sweden and a combined cohort. Participants were self-reported Caucasian and physically active. The combined cohort consisted of 265 asymptomatic controls (POL-CON=150; SWD-CON=116); 237 ACL rupture cases (POL-ACLR=141; SWD-ACLR=95) and a subgroup of 135 non-contact ACL ruptures (POL-NON=54; SWD-NON=79). Participants were genotyped for rs2291826 A>G and rs2291827 G>A and data were analysed using R, with p<0.05. Results Strong correlations were found between mass and BMI across all cohorts (r=0.78–0.81), suggesting these traits may influence injury risk. Sex-mass and sex-height correlations were consistent, with a strong negative correlation between sex and height in the Swedish cohort (r=-0.75). No positive correlations were found between the HSPG2 variants and anthropometric traits, except a moderate negative correlation between rs2291826A>G and height in the Swedish cohort (r=-0.019, p<0.009), suggesting possible genotype effect on height. Conclusion Mass and BMI were highlighted as potential risk factors for ACL rupture. Height-mass relationships varied by sex and population, suggesting both genetics and environment impact injury patterns. Further testing of the variants may clarify their role in ACL injury variability.

Background Anterior cruciate ligament rupture (ACL-R) is a common sports injury influenced by biomechanical, anthropometric, environmental, and genetic factors. Collagen gene polymorphisms have been implicated in ACL-R, with a whole-genome sequencing twin study highlighting COL12A1 rs970547 C>T as a variant of interest. However, the additive impact of the anthropometric traits and COL12A1 on ACL-R susceptibility remains unexplored. Objectives To investigate the additive effect of anthropometric traits and COL12A1 rs970547 C>T on ACL-R susceptibility in an Australian and South African cohort with the a priori hypothesis that female T/T carriers were at an increased risk. Sample and Methods The study included ACL-R cases (Australia n = 354; South Africa n = 252) and controls (Australia n = 84; South Africa n = 232). COL12A1 rs970547 C>T SNP was genotyped using TaqMan® assays. Anthropometric traits were sex-stratified/standardised. Logistic regression and principal component analyses were assessed. Results No significant genetic associations were found for COL12A1 rs970547 C>T in the i) individual/combined and ii) male/female cohorts. PCA revealed clustering of anthropometrics in PC1–PC2, with PC3 being driven exclusively by rs970547 in each cohort. Conclusion No associations were noted between the COL12A1 rs970547 T/T genotype and ACL-R risk. PCA, however, indicated that rs970547 may hold biological significance in ACL-R susceptibility, highlighting the complex interplay of genetic and anthropometric traits.

Background/Objectives: Types I, V, and XI collagen gene variants have been reported to associate with measurements of knee joint laxity and/or absolute knee ligament length changes. Type XII collagen and tenascin C are also ligament structural proteins whose expression is regulated by mechanical loading. This study investigated whether COL12A1 and TNC variants are associated with knee laxity and/or ligament length changes. Methods: Genu recurvatum, anterior–posterior tibial translation, external–internal tibial rotation, and ligament length changes were measured in 128 healthy participants. They were genotyped for COL12A1 (rs970547) and TNC (rs1061494, rs2104772, rs1138545). Results: Both the COL12A1 AA and TNC rs1061494 TT genotypes were associated with decreased external (p = 0.007, p = 0.010) and internal (p = 0.025, p = 0.002) rotation, as well as slack (p = 0.033, p = 0.014), in the dominant leg. Both genotypes, together with sex, weight, and/or COL1A1 genotypes, explained 26% and 32% of the variance in external and internal rotation, respectively. The TNC genotype, sex, and BMI explained 23% of the variance in slack. The COL12A1 AA and the TNC rs1061494 TT genotypes were associated with smaller changes in the MCL (aMCL: COL12A1 p = 0.009, TNC p = 0.045; iMCL: COL12A1 p = 0.004, TNC p = 0.043; pMCL: COL12A1 p = 0.003, TNC p = 0.067; aDMCL: COL12A1 p = 0.007, TNC p = 0.020; pDMCL: COL12A1 p = 0.007, TNC p = 0.023) and/or LCL (COL12A1 p = 0.652, TNC p = 0.049) lengths within the dominant knee. The TNC rs1061494 CC genotype was associated with larger changes in the non-dominant anterior (p = 0.021) and posterior (p < 0.001) ACL bundle lengths. Conclusions: These findings suggest that COL12A1 and TNC variants are associated with internal–external tibial rotation and knee ligament length changes in healthy individuals.

OBJECTIVES:To investigate associations between genetic variants within COLGALT1, COL1A1, COL3A1, COL5A1, KDR, MIR608, MMP3, NID1, TIMP2 and VEGFA and injury history in elite male rugby athletes. DESIGN:A case-control genetic association study was conducted on 184 elite male rugby athletes. METHODS:Participants were genotyped for 13 genetic polymorphisms previously associated with soft tissue injury using standard PCR assays. Injury data were collected via a self-reported injury-history questionnaire. Single-locus association and Total Genotype Score (TGS) analyses were conducted using χ2 tests. In addition, multifactor dimensionality reduction and inferred haplotype analysis were used to identify genetic interactions. RESULTS:The TT genotype of MMP3 rs679620 was underrepresented in the non-injured ligament group compared to the ligament sprain and ligament rupture groups (10 %, 32 %, 25 %; P < 0.04, respectively). The T allele of MMP3 rs679620 was overrepresented in the non-injured tendon group compared to the tendinopathy group (50 %, 38 %; P < 0.02). The proportion of C allele carriers of COL5A1 rs12722 was higher in the tendon rupture group than the non-injured tendon group (96 %, 75 %; P < 0.02). Furthermore, the T-C inferred haplotype frequency of COL5A1 rs12722 and COL5A1 rs3196378 was higher in the tendon rupture, ligament sprain and total injured athlete groups compared to their respective non-injured groups (P < 0.02). CONCLUSIONS:This study is the first to identify associations between MMP3 rs679620 and COL5A1 rs12722 and soft-tissue injury history in elite male rugby athletes. These findings support the growing evidence that soft-tissue injury could be influenced by an athlete's genetic predisposition.

Integrin complexes facilitate cell communication, playing a role in ligament homeostasis. ITGB2 rs2230528 (C/T) was implicated in anterior cruciate ligament rupture (ACL) risk in a South African cohort. Identifying biologically significant DNA signatures in the predisposition to ACL rupture risk remains important towards understanding mechanisms of ACL ruptures. ITGB2 is essential for the activation of important biological pathways regulated by structural components such as collagens and biomechanical components such as vasculo-endothelial growth factors. This study tested the association of (i) ITGB2 rs2230528 and (ii) allele-allele combinations of ITGB2's network partners (COL5A1 rs12722 C/T, VEGFA rs699947 C/A and VEGFA rs2010963 G/C) with ACL rupture risk. The genetic study was conducted in a combined cohort [n=1279: uninjured controls (CON), n=548; ACL ruptures (ACL), n=731; subgroup with non-contact mechanism of ACL ruptures (NON, n=425)] recruited from Australia, Poland, Sweden and South Africa. The combined cohort, rs2230528 TT (best fit model) was significantly over-represented in the ACL (p=8.00 × 10-8; OR:3.21; 95% CI:2.10-4.89, AIC=1549) and NON (p=1.59 × 10-6; OR:3.11; 95% CI:1.97-4.91, AIC=1191) groups compared to CON. ITGB2 rs2230528-COL5A1 rs12722-VEGFA rs699947-VEGFA rs2010963, the C-C-A-G and C-T-C-G combinations were significantly associated with reduced ACL risk. This study provided additional evidence highlighting ITGB2 as potentially being associated with ACL ruptures even though the gene-gene combinations had a small effect size. Integrins containing the b2 subunit together with its key extracellular matrix components (type V collagen and VEGFA) are potential therapeutic targets for ACL ruptures and potentially other connective tissue-related conditions.

Success in long-distance running relies on multiple factors including oxygen utilisation and lactate metabolism, and genetic associations with athlete status suggest elite competitors are heritably predisposed to superior performance. The Gly allele of the PPARGC1A Gly482Ser rs8192678 polymorphism has been associated with endurance athlete status and favourable aerobic training adaptations. However, the association of this polymorphism with performance amongst long-distance runners remains unclear. Accordingly, this study investigated whether rs8192678 was associated with elite status and competitive performance of long-distance runners. Genomic DNA from 656 Caucasian participants including 288 long-distance runners (201 men, 87 women) and 368 non-athletes (285 men, 83 women) was analysed. Medians of the 10 best UK times (Top10) for 10 km, half-marathon and marathon races were calculated, with all included athletes having personal best (PB) performances within 20% of Top10 (this study's definition of "elite"). Genotype and allele frequencies were compared between athletes and non-athletes, and athlete PB compared between genotypes. There were no differences in genotype frequency between athletes and non-athletes, but athlete Ser allele carriers were 2.5% faster than Gly/Gly homozygotes (p = 0.030). This study demonstrates that performance differences between elite long-distance runners are associated with rs8192678 genotype, with the Ser allele appearing to enhance performance.

BACKGROUND:The 56km Two Oceans ultra-marathon (TOM), in Cape Town, South Africa, was cancelled in 2020 and 2021 because of the COVID-19 pandemic. Since most other road running events were also cancelled during this period, we hypothesized that most athletes who entered TOM 2022 would be inadequately trained, which would negatively affect performance. However, many world records were broken post-lockdown, and therefore the performance, specifically of the elite athletes, during TOM might actually improve. The aim of this analysis was to evaluate the impact of the COVID-19 pandemic on performance in TOM 2022 compared to the 2018 event.METHODS:Performance data during the two events, as well as the 2021 Cape Town marathon, was extracted from public databases.RESULTS:Fewer athletes entered TOM 2022 (N.=4741) compared to TOM 2018 (N.=11,702), of which more were male (2022: 74.5% vs. 2018: 70.4%, P<0.05) and in the 40+ age-group categories. Compared to 2018 (11.3%), fewer athletes did not finish TOM 2022 (3.1%). Only 10.2% of the finishers completed the 2022 race during the last 15-minutes prior to the cut-off, compared to 18.3% in 2018. There were no differences in the average 2022 finishing time of the subset of 290 athletes whose times were compared to their 2018 performance. There was no difference in the TOM 2022 performance of athletes who had completed the 2021 Cape Town marathon, 6-months earlier, when compared to those who had not entered the marathon.CONCLUSIONS:Although there were fewer entrants, most athletes who entered knew that they were adequately trained to complete TOM 2022, with the top runners breaking course records. There was therefore no impact of the pandemic on performance during TOM 2022.

IntroductionSeveral direct-to-consumer (DTC) genetic testing companies have emerged that claim to be able to test for susceptibility for musculoskeletal injuries. Although there are several publications on the emergence of this industry, none have critically evaluated the evidence for the use of genetic polymorphisms in commercial tests. The aim of this review was to identify, where possible, the polymorphisms and to evaluate the current scientific evidence for their inclusion. ResultsThe most common polymorphisms included COL1A1 rs1800012, COL5A1 rs12722, and GDF5 rs143383. The current evidence suggests that it is premature or even not viable to include these three polymorphisms as markers of injury risk. A unique set of injury-specific polymorphisms, which do not include COL1A1, COL5A1, or GDF5, identified from genome-wide association studies (GWAS) is used by one company in their tests for 13 sports injuries. However, of the 39 reviewed polymorphisms, 22 effective alleles are rare and absent in African, American, and/or Asian populations. Even when informative in all populations, the sensitivity of many of the genetic markers was low and/or has not been independently validated in follow-up studies. ConclusionsThe current evidence suggests it is premature to include any of the reviewed polymorphisms identified by GWAS or candidate gene approaches in commercial genetic tests. The association of MMP7 rs1937810 with Achilles tendon injuries, and SAP30BP rs820218 and GLCCI1 rs4725069 with rotator cuff injuries does warrant further investigation. Based on current evidence, it remains premature to market any commercial genetic test to determine susceptibility to musculoskeletal injuries.

We developed a Biomedical Knowledge Graph model that is phenotype and biological function-aware through integrating knowledge from multiple domains in a Neo4j, graph database. All known human genes were assessed through the model to identify potential new risk genes for anterior cruciate ligament (ACL) ruptures and Achilles tendinopathy (AT). Genes were prioritised and explored in a case-control study comparing participants with ACL ruptures (ACL-R), including a sub-group with non-contact mechanism injuries (ACL-NON), to uninjured control individuals (CON). After gene filtering, 3376 genes, including 411 genes identified through previous whole exome sequencing, were found to be potentially linked to AT and ACL ruptures. Four variants were prioritised: HSPG2:rs2291826A/G, HSPG2:rs2291827G/A, ITGB2:rs2230528C/T and FGF9:rs2274296C/T. The rs2230528 CC genotype was over-represented in the CON group compared to ACL-R (p < 0.001) and ACL-NON (p < 0.001) and the TT genotype and T allele were over-represented in the ACL-R group and ACL-NON compared to CON (p < 0.001) group. Several significant differences in distributions were noted for the gene-gene interactions: (HSPG2:rs2291826, rs2291827 and ITGB2:rs2230528) and (ITGB2:rs2230528 and FGF9:rs2297429). This study substantiates the efficiency of using a prior knowledge-driven in silico approach to identify candidate genes linked to tendon and ACL injuries. Our biomedical knowledge graph identified and, with further testing, highlighted novel associations of the ITGB2 gene which has not been explored in a genetic case control association study, with ACL rupture risk. We thus recommend a multistep approach including bioinformatics in conjunction with next generation sequencing technology to improve the discovery potential of genomics technologies in musculoskeletal soft tissue injuries.HighlightsA biomedical knowledge graph was modelled for musculoskeletal soft tissue injuries to efficiently identify candidate genes for genetic susceptibility analyses.The biomedical knowledge graph and sequencing data identified potential biologically relevant variants to explore susceptibility to common tendon and ligament injuries. Specifically genetic variants within the ITGB2 and FGF9 genes were associated with ACL risk.Novel allele combinations (HSPG2-ITGB2 and ITGB2-FGF9) showcase the potential effect of ITGB2 in influencing risk of ACL rupture.

Objective: Concussions are common match injuries in elite rugby, and reports exist of reduced cognitive function and long-term health consequences that can interrupt or end a playing career and produce continued ill health. The aim of this study was to investigate the association between elite rugby status and 8 concussion-associated risk polymorphisms. We hypothesized that concussion-associated risk genotypes and alleles would be underrepresented in elite rugby athletes compared with nonathletes. Design: A case–control genetic association study. Setting: Institutional (university). Participants: Elite White male rugby athletes [n = 668, mean (SD) height 1.85 (0.07) m, mass 102 (12) kg, and age 29 (7) years] and 1015 nonathlete White men and women (48% men). Interventions: Genotype was the independent variable, obtained by PCR of genomic DNA using TaqMan probes. Main Outcome Measure: Elite athlete status with groups compared using χ 2 and odds ratio (OR). Results: The COMT rs4680 Met/Met (AA) genotype, Met allele possession, and Met allele frequency were lower in rugby athletes (24.8%, 74.6%, and 49.7%, respectively) than nonathletes (30.2%, 77.6%, and 54.0%; P < 0.05). The Val/Val (GG) genotype was more common in elite rugby athletes than nonathletes (OR 1.39, 95% confidence interval 1.04-1.86). No other polymorphism was associated with elite athlete status. Conclusions: Elite rugby athlete status is associated with COMT rs4680 genotype that, acting pleiotropically, could affect stress resilience and behavioral traits during competition, concussion risk, and/or recovery from concussion. Consequently, assessing COMT rs4680 genotype might aid future individualized management of concussion risk among athletes.

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.

Background: Joint laxity is a multifactorial phenotype with a heritable component. Type I collagen gene (COL1A1) mutations cause connective tissue disorders with joint hypermobility as a clinical feature, while variants within COL1A1 and type III collagen gene (COL3A1) are associated with musculoskeletal injuries. The aim of this study was to investigate whether COL1A1 and COL3A1 variants are associated with measurements of non-dominant knee joint laxity and computed ligament length changes.Methods: 106 moderately active uninjured participants were assessed for genu recurvatum, anterior-posterior tibial translation, external-internal tibial rotation and calculated ligament length changes during knee rota-tion. Participants were genotyped for COL1A1 rs1107946, rs1800012 and COL3A1 rs1800255.Findings: The COL1A1 rs1107946 GG genotype had significantly larger external rotation [GG: 5.7 degrees (4.9 degrees ;6.4 degrees) vs GT: 4.6 degrees (4.2 degrees ;5.5 degrees), adjusted P = 0.014], internal rotation [GG: 5.9 degrees (5.3 degrees ;6.6 degrees) vs GT: 5.4 degrees (4.7 degrees ;6.2 degrees), adjusted P = 0.014], and slack [GG: 18.2 degrees +/- 3.2 degrees vs GT: 16.1 degrees +/- 3.1 degrees, adjusted P = 0.014]. The GG genotype at both COL1A1 variants had significantly larger active displacement [GG + GG: 6.0 mm (3.8 mm;8.0 mm) vs other genotype combinations: 4.0 mm (2.5 mm;6.0 mm), P < 0.001] and maximum displacement [GG + GG: 8.0 mm (6.9 mm;10.6 mm) vs other genotype combinations: 6.0 mm (5.0 mm;9.0 mm), P = 0.003]. COL1A1 rs1107946 significantly contributed to increased external and internal rotation in multilinear regression models, while both COL1A1 variants, significantly contributed to increased active displacement and slack. Larger medial and lateral cruciate ligament length changes were reported in participants with GG genotypes at both COL1A1 variants.Interpretation: These findings suggest that the COL1A1 variants are associated with knee rotational laxity and changes in ligament length.

Predisposition to anterior cruciate ligament (ACL) rupture is multi-factorial, with variation in the genome considered a key intrinsic risk factor. Most implicated loci have been identified from candidate gene-based approach using case-control association settings. Here, we leverage a hypothesis-free whole genome sequencing in two two unrelated families (Family A and B) each with twins with a history of recurrent ACL ruptures acquired playing rugby as their primary sport, aimed to elucidate biologically relevant function-altering variants and genetic modifiers in ACL rupture. Family A monozygotic twin males (Twin 1 and Twin 2) both sustained two unilateral non-contact ACL ruptures of the right limb while playing club level touch rugby. Their male sibling sustained a bilateral non-contact ACL rupture while playing rugby union was also recruited. The father had sustained a unilateral non-contact ACL rupture on the right limb while playing professional amateur level football and mother who had participated in dancing for over 10 years at a social level, with no previous ligament or tendon injuries were both recruited. Family B monozygotic twin males (Twin 3 and Twin 4) were recruited with Twin 3 who had sustained a unilateral non-contact ACL rupture of the right limb and Twin 4 sustained three non-contact ACL ruptures (two in right limb and one in left limb), both while playing provincial level rugby union. Their female sibling participated in karate and swimming activities; and mother in hockey (4 years) horse riding (15 years) and swimming, had both reported no previous history of ligament or tendon injury. Variants with potential deleterious, loss-of-function and pathogenic effects were prioritised. Identity by descent, molecular dynamic simulation and functional partner analyses were conducted. We identified, in all nine affected individuals, including twin sets, non-synonymous SNPs in three genes: COL12A1 and CATSPER2 , and KCNJ12 that are commonly enriched for deleterious, loss-of-function mutations, and their dysfunctions are known to be involved in the development of chronic pain, and represent key therapeutic targets. Notably, using Identity By Decent (IBD) analyses a long shared identical sequence interval which included the LINC01250 gene, around the telomeric region of chromosome 2p25.3, was common between affected twins in both families, and an affected brother’. Overall gene sets were enriched in pathways relevant to ACL pathophysiology, including complement/coagulation cascades (p = 3.0e-7), purine metabolism (p = 6.0e-7) and mismatch repair (p = 6.9e-5) pathways. Highlighted, is that this study fills an important gap in knowledge by using a WGS approach, focusing on potential deleterious variants in two unrelated families with a historical record of ACL rupture; and providing new insights into the pathophysiology of ACL, by identifying gene sets that contribute to variability in ACL risk.

Joint laxity is a multifactorial phenotype with a heritable component. Mutations or common polymorphisms within the α1(V) (COL5A1), α1(XI) (COL11A1) and α2(XI) (COL11A2) collagen genes have been reported or proposed to associate with joint hypermobility, range of motion and/or genu recurvatum. The aim of this study was to investigate whether polymorphisms within these collagen-encoding genes are associated with measurements of knee joint laxity and computed ligament length changes within the non-dominant leg. One hundred and six healthy participants were assessed for genu recurvatum (knee hyperextension), anterior-posterior tibial translation, external-internal tibial rotation and ligament length changes during knee rotation of their non-dominant leg. Participants were genotyped for COL5A1 rs12722 (T/C), COL11A1 rs3753841 (C/T), COL11A1 rs1676486 (T/C) and COL11A2 rs1799907 (A/T). The genotype-genotype combination of any two or more of the four COL5A1 rs12722 CC, COL11A1 rs3753841 CC, COL11A1 rs1676486 TT and COL11A2 rs1799907 AA genotypes was associated with decreased active and passive knee hyperextension. These genotype-genotype combinations, including sex (male), increased age and decreased body mass collectively, also contributed to decreased passive knee hyperextension. These findings suggest that COL5A1, COL11A1 and COL11A2 gene-gene interactions are associated with knee hyperextension measurements of the non-dominant leg of healthy individuals.

There is growing evidence of genetic contributions to tendon and ligament pathologies. Given the high incidence and severity of tendon and ligament injuries in elite rugby, we studied whether 13 gene polymorphisms previously associated with tendon/ligament injury were associated with elite athlete status. Participants from the RugbyGene project were 663 elite Caucasian male rugby athletes (RA) (mean (standard deviation) height 1.85 (0.07) m, mass 101 (12) kg, age 29 (7) yr), including 558 rugby union athletes (RU) and 105 rugby league athletes. Non-athletes (NA) were 909 Caucasian men and women (56% female; height 1.70 (0.10) m, mass 72 (13) kg, age 41 (23) yr). Genotypes were determined using TaqMan probes and groups compared using Χ2 and odds ratio (OR). COLGALT1 rs8090 AA genotype was more frequent in RA (27%) than NA (23%; P = 0.006). COL3A1 rs1800255 A allele was more frequent in RA (26%) than NA (23%) due to a greater frequency of GA genotype (39% vs 33%). For MIR608 rs4919510, RA had 1.7 times the odds of carrying the CC genotype compared to NA. MMP3 rs591058 TT genotype was less common in RA (25.1%) than NA (31.2%; P < 0.04). For NID1 rs4660148, RA had 1.6 times the odds of carrying the TT genotype compared to NA. It appears that elite rugby athletes have an inherited advantage that contributes to their elite status, possibly via resistance to soft tissue injury. These data may, in future, assist personalised management of injury risk amongst athletes.Highlights The elite rugby athletes we studied had differing genetic characteristics to non-athletes regarding genetic variants previously associated with soft-tissue injury risk.COLGALT1 rs8090, COL3A1 rs1800255, MIR608 rs4919510, MMP3 rs591058 and NID1 rs4660148 were all associated with elite status in rugby.We propose that elite rugby athletes might possess an inherited resistance to soft tissue injury, which has enabled them to achieve elite status despite exposure to the high-risk environment of elite rugby.

A significant proportion of patients requiring musculoskeletal management present with tendon and ligament pathology. Our understanding of the intrinsic and extrinsic mechanisms that lead to such disabilities is increasing. However, the complexity underpinning these interactive multifactorial elements is still not fully characterised. Evidence highlighting the genetic components, either reducing or increasing susceptibility to injury, is increasing. This review examines the present understanding of the role genetic variations contribute to tendon and ligament injury risk. It examines the different elements of tendon and ligament structure and considers our knowledge of genetic influence on form, function, ability to withstand load, and undertake repair or regeneration. The role of epigenetic factors in modifying gene expression in these structures is also explored. It considers the challenges to interpreting present knowledge, the requirements, and likely pathways for future research, and whether such information has reached the point of clinical utility.

Part 1 of this genetic association series highlighted several genetic variants independently associated with elite status in rugby. However, it is highly likely that the genetic influence on elite status is polygenic due to the interaction of multiple genes. Therefore, the aim of the present study was to investigate whether polygenic profiles of elite rugby athletes differed from non-athletes utilising 13 genetic polymorphisms previously associated with tendon/ligament injury. Total genotype score (TGS) was calculated and multifactor dimensionality reduction (MDR) was used to calculate SNP-SNP epistasis interactions. Based on our elite rugby data from Part 1, mean TGS was significantly higher in elite rugby athletes (52.1 ± 10.7) than non-athletes (48.7 ± 10.8). There were more elite rugby athletes (54%) within the upper TGS quartile, and fewer (46%) within the lower quartile, compared to non-athletes (31% and 69%, respectively; P = 5·10-5), and the TGS was able to distinguish between elite rugby athletes and non-athletes (area under the curve = 0.59; 95% confidence interval 0.55-0.63; P = 9·10-7). Furthermore, MDR identified a three-SNP model of COL5A1 rs12722, COL5A1 rs3196378 and MIR608 rs4919510 that was best able to predict elite athlete status, with a greater frequency of the CC-CC-CC genotype combination in elite rugby athletes (9.8%) than non-athletes (5.3%). We propose that elite rugby athletes possess "preferable" musculoskeletal soft-tissue injury-associated polygenic profiles that have helped them achieve success in the high injury risk environment of rugby. These data may, in future, have implications for the individual management of musculoskeletal soft-tissue injury.HighlightsElite rugby athletes have preferable polygenic profiles to non-athletes in terms of genetic variants previously associated with musculoskeletal soft-tissue injury.The total genotype score was able to distinguish between elite rugby athletes and non-athletes.COL5A1 rs12722, COL5A1 rs3196378 and MIR608 rs4919510 produced the best model for predicting elite athlete status.We propose that elite rugby athletes may have an inherited advantage to achieving elite status due to an increased resistance to soft-tissue injury.

Altered central pain mechanisms is a feature of other chronic pain states and upper limb tendinopathies. It is uncertain whether the same applies to chronic Achilles tendinopathy (AT).