Are commercial genetic injury tests premature?

INTRODUCTION: Several 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. RESULTS: The 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. CONCLUSIONS: The 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.

Regulatory VCAN polymorphism is associated with shoulder pain and disability in breast cancer survivors.

BACKGROUND AND PURPOSE: Shoulder morbidity following breast cancer treatment is multifactorial. Despite several treatment- and patient-related factors being implicated, unexplained inter-individual variability exists in the development of such morbidity. Given the paucity of relavant genetic studies, we investigate the role of polymorphisms in candidate proteoglycan genes. PATIENTS AND METHODS: We conducted a cross-sectional study on 254 South African breast cancer survivors, to evaluate associations between shoulder pain/disability and ten single nucleotide polymorphisms (SNPs) within four proteoglycan genes: ACAN (rs1126823 G>A, rs1516797 G>T, rs2882676 A>C); BGN (rs1042103 G>A, rs743641 A>T, rs743642 G>T); DCN rs516115 C>T; and VCAN (rs11726 A>G, rs2287926 G>A, rs309559). Participants were grouped into no-low and moderate-high shoulder pain/disability based on total pain/disability scores: < 30 and ≥ 30, respectively using the Shoulder Pain and Disability Index (SPADI). RESULTS: The GG genotype of VCAN rs11726 was independently associated with an increased risk of being in the moderate-to-high shoulder pain (P = 0.005, OR = 2.326, 95% CI = 1.259-4.348) or disability (P = 0.011, OR = 2.439, 95% CI = 1.235-4.762) categories, after adjusting for participants' age. In addition, the T-T-G inferred allele combination of BGN (rs74364-rs743642)-VCAN rs11726 was associated with an increased risk of being in the moderate-to-high shoulder disability category (0 = 0.002, OR = 2.347, 95% CI = 1.215-4.534). CONCLUSION: Our study is first to report that VCAN rs11726, independently or interacting with BGN polymorphisms, is associated with shoulder pain or disability in breast cancer survivors. Whereas our findings suggest an involvement of proteoglycans in the etiology of shoulder pain/disability, further studies are recommended.

MicroRNA Profile and Adaptive Response to Exercise Training: A Review.

MicroRNAs are small non-coding regulatory RNAs which may be released into the systemic circulation as a consequence of the body's adaptation to exercise. The expression profile of circulating miRNAs (ci-miRNAs) has been proposed as a potential diagnostic biomarker for adaptive responses of particular systems to physical exertion. Several miRNAs are recognized as regulators of signalling pathways such as the IGF1/PI3K/AKT/mTOR axis, relevant to exercise adaptation. MicroRNA levels may fluctuate depending on training type/exercise regimen in correlation with phenotypic features such as VO2 max. Muscle-specific miRNAs have been proposed as regulators of skeletal muscle/myocardial interactions during physical exertion, thereby facilitating adaptation. Differential expression of miRNAs may relate to molecular patterns of communication triggered during/after exercise as response, recovery and adaptation mechanisms to training load. This review highlights recent findings and the potential significance of specific miRNAs in the process of exercise adaptation. Altered ci-miRNA profiles following exercise suggest that they may be useful biomarkers of health and adaptation to intervention strategies. Identification of the concert of miRNA expression signatures together with their targets is critical towards understanding gene regulation in this context. Understanding how the external environment influences gene expression via miRNAs will provide insight into potential therapeutic target strategies for disease.

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

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

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

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

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

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

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

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

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

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

Genomic medicine and risk prediction across the disease spectrum.

Genomic medicine is based on the knowledge that virtually every medical condition, disease susceptibility or response to treatment is caused, regulated or influenced by genes. Genetic testing may therefore add value across the disease spectrum, ranging from single-gene disorders with a Mendelian inheritance pattern to complex multi-factorial diseases. The critical factors for genomic risk prediction are to determine: (1) where the genomic footprint of a particular susceptibility or dysfunction resides within this continuum, and (2) to what extent the genetic determinants are modified by environmental exposures. Regarding the small subset of highly penetrant monogenic disorders, a positive family history and early disease onset are mostly sufficient to determine the appropriateness of genetic testing in the index case and to inform pre-symptomatic diagnosis in at-risk family members. In more prevalent polygenic non-communicable diseases (NCDs), the use of appropriate eligibility criteria is required to ensure a balance between benefit and risk. An additional screening step may therefore be necessary to identify individuals most likely to benefit from genetic testing. This need provided the stimulus for the development of a pathology-supported genetic testing (PSGT) service as a new model for the translational implementation of genomic medicine in clinical practice. PSGT is linked to the establishment of a research database proven to be an invaluable resource for the validation of novel and previously described gene-disease associations replicated in the South African population for a broad range of NCDs associated with increased cardio-metabolic risk. The clinical importance of inquiry concerning family history in determining eligibility for personalized genotyping was supported beyond its current limited role in diagnosing or screening for monogenic subtypes of NCDs. With the recent introduction of advanced microarray-based breast cancer subtyping, genetic testing has extended beyond the genome of the host to also include tumor gene expression profiling for chemotherapy selection. The decreasing cost of next generation sequencing over recent years, together with improvement of both laboratory and computational protocols, enables the mapping of rare genetic disorders and discovery of shared genetic risk factors as novel therapeutic targets across diagnostic boundaries. This article reviews the challenges, successes, increasing inter-disciplinary integration and evolving strategies for extending PSGT towards exome and whole genome sequencing (WGS) within a dynamic framework. Specific points of overlap are highlighted between the application of PSGT and exome or WGS, as the next logical step in genetically uncharacterized patients for whom a particular disease pattern and/or therapeutic failure are not adequately accounted for during the PSGT pre-screen. Discrepancies between different next generation sequencing platforms and low concordance among variant-calling pipelines caution against offering exome or WGS as a stand-alone diagnostic approach. The public reference human genome sequence (hg19) contains minor alleles at more than 1 million loci and variant calling using an advanced major allele reference genome sequence is crucial to ensure data integrity. Understanding that genomic risk prediction is not deterministic but rather probabilistic provides the opportunity for disease prevention and targeted treatment in a way that is unique to each individual patient.

Biological variation in musculoskeletal injuries: current knowledge, future research and practical implications.

Evidence from familial and genetic association studies have reported that DNA sequence variants play an important role, together with non-genetic factors, in the aetiology of both exercise-associated and occupational-associated acute and chronic musculoskeletal soft tissue injuries. The associated variants, which have been identified to date, may contribute to the interindividual variation in the structure and, by implication, mechanical properties of the collagen fibril and surrounding matrix within musculoskeletal soft tissues, as well as their response to mechanical loading and other stimuli. Future work should focus on the establishment of multidisciplinary international consortia for the identification of biologically relevant variants involved in modulating injury risk. These consortia will improve the limitations of the published hypothesis-driven genetic association studies, since they will allow resources to be pooled in recruiting large well-characterised cohorts required for whole-genome screening. Finally, clinicians and coaches need to be aware that many direct-to-consumer companies are currently marketing genetic tests directly to athletes without it being requested by an appropriately qualified healthcare professional, and without interpretation alongside other clinical indicators or lifestyle factors. These specific genetic tests are premature and are not necessarily required to evaluate susceptibility to musculoskeletal soft tissue injury. Current practice should rather consider susceptibility through known risk factors such as a positive family history of a specific injury, a history of other tendon and/or ligament injuries and participation in activities associated with the specific musculoskeletal injuries. Potential susceptible athletes may then be individually managed to reduce their risk profile.

A variant within the AQP1 3'-untranslated region is associated with running performance, but not weight changes, during an Ironman Triathlon.

The objective of this study was to test the association of the rs1049305 (G > C) variant within the 3'-untranslated region of the aquaporin 1 gene, AQP1, with changes in body weight, post-race serum sodium concentration and performance in Ironman triathletes. Five hundred and four male Ironman triathletes were genotyped for the rs1049305 variant within the AQP1 gene. Change in pre- and post-race body weight was calculated for 470 triathletes and used as a proxy for changes in body fluid during the race, as well as to divide triathletes into biologically relevant weight-loss groups (0-3%, 3-5% and >5%). There were no rs1049305 genotype effects on post-race serum sodium concentrations (P = 0.647), pre-race weight (P = 0.610) nor relative weight change during the Ironman Triathlons (P = 0.705). In addition, there were no significant differences in genotype (P = 0.640) nor allele (P = 0.643) distributions between the weight loss groups. However, triathletes who carry a C-allele were found to complete the 42.2-km run stage faster (mean 286, s = 49 min) than triathletes with a GG genotype (mean 296, s = 47 min; P = 0.032). The AQP1 rs1049305 variant is associated with running performance, but not relative body weight change, during the 2000, 2001 and 2006 South African Ironman Triathlons.

Risk factors for sports concussion: an evidence-based systematic review.

Concussion is a common sports injury with approximately 1.6-3.8 million sport-related concussions reported in the USA annually. Identifying risk factors may help in preventing these injuries. This systematic review aims to identify such risk factors. Three electronic databases; ScienceDirect, PubMed and SpringerLink, were searched using the keywords 'RISK FACTORS' or 'PREDISPOSITION' in conjunction with 'SPORT' and 'CONCUSSION'. Based on the inclusion and exclusion criteria, 13 628 identified titles were independently analysed by two of the authors to a final list of 86 articles. Only articles with a level of evidence of I, II and III were included according to robust study design and data analysis. The level of certainty for each risk factor was determined. A high level of certainty for increased risk of a subsequent concussion in athletes sustaining more than one previous concussion was reported in 10 of 13 studies. Further, a high level of certainty was assigned to match play with all 29 studies reporting an increased concussion risk during matches. All other risk factors were evaluated as having a low level of certainty. Although several risk factors were identified from the appraised studies, prospective cohort studies, larger sample sizes, consistent and robust measures of risk should be employed in future research.

Genes encoding proteoglycans are associated with the risk of anterior cruciate ligament ruptures.

BACKGROUND: Genetic variants within genes involved in fibrillogenesis have previously been implicated in anterior cruciate ligament (ACL) injury susceptibility. Proteoglycans also have important functions in fibrillogenesis and maintaining the structural integrity of ligaments. Genes encoding proteoglycans are plausible candidates to be investigated for associations with ACL injury susceptibility; polymorphisms within genes encoding the proteoglycans aggrecan (ACAN), biglycan (BGN), decorin (DCN), fibromodulin (FMOD) and lumican (LUM) were examined. METHODS: A case-control genetic association study was conducted. 227 participants with surgically diagnosed ACL ruptures (ACL group) and 234 controls without any history of ACL injury were genotyped for 10 polymorphisms in 5 proteoglycan genes. Inferred haplotypes were constructed for specific regions. RESULTS: The G allele of ACAN rs1516797 was significantly under-represented in the controls (p=0.024; OR=0.72; 95% CI 0.55 to 0.96) compared with the ACL group. For DCN rs516115, the GG genotype was significantly over-represented in female controls (p=0.015; OR=9.231; 95%CI 1.16 to 73.01) compared with the ACL group and the AA genotype was significantly under-represented in controls (p=0.013; OR=0.33; 95% CI 0.14 to 0.78) compared with the female non-contact ACL injury subgroup. Haplotype analyses implicated regions overlapping ACAN (rs2351491 C>T-rs1042631 T>C-rs1516797 T>G), BGN (rs1126499 C>T-rs1042103 G>A) and LUM-DCN (rs2268578 T>C-rs13312816 A>T-rs516115 A>G) in ACL injury susceptibility. CONCLUSIONS: These independent associations and haplotype analyses suggest that regions within ACAN, BGN, DCN and a region spanning LUM-DCN are associated with ACL injury susceptibility. Taking into account the functions of these genes, it is reasonable to propose that genetic sequence variability within the genes encoding proteoglycans may potentially modulate the ligament fibril properties.

Variants within the COMP and THBS2 genes are not associated with Achilles tendinopathy in a case-control study of South African and Australian populations.

Cartilage oligomeric matrix protein is a structural protein of the extracellular matrix, while thrombospondin-2 is a matricellular protein involved in cell-matrix interactions. Recent studies have shown that genetic variation is a significant risk factor for Achilles tendinopathy, and the genes encoding cartilage oligomeric matrix protein (COMP) and thrombospondin-2 (THBS2) were identified as good candidate genes for association with Achilles tendinopathy. This study aimed to test the association of sequence variants within these candidate genes with the risk of Achilles tendinopathy in participants from South Africa (SA) and Australia (AUS). Three-hundred and forty (133 SA; 207 AUS) control participants with no history of Achilles tendinopathy and 178 (94 SA; 84 AUS) participants clinically diagnosed with Achilles tendinopathy were genotyped for five single nucleotide polymorphisms within the COMP and THBS2 genes in this case-control study. There was no difference in genotype distributions between control and tendinopathy groups for either the THBS2 variants rs9505888, rs6422747 and rs9283850, or the COMP variants rs730079 and rs28494505 in the SA and AUS populations. As the selection of COMP and THBS2 as candidate genes was hypothesis driven, based on biological function, the possibility that other variants within these genes are associated with Achilles tendinopathy cannot be excluded.

Association of type XI collagen genes with chronic Achilles tendinopathy in independent populations from South Africa and Australia.

BACKGROUND: Type XI collagen, which is expressed in developing tendons and is encoded by the COL11A1, COL11A2 and COL2A1 genes, shares structural and functional homology with type V collagen, which plays an important role in collagen fibril assembly. We investigated the association of these three polymorphisms with Achilles tendinopathy (AT) and whether these polymorphisms interact with COL5A1 to modulate the risk of AT. METHODS: 184 participants diagnosed with chronic AT (TEN) and 338 appropriately matched asymptomatic controls (CON) were genotyped for the three polymorphisms. RESULTS: Although there were no independent associations with AT, the TCT pseudohaplotype constructed from rs3753841 (T/C), rs1676486 (C/T) and rs1799907 (T/A) was significantly over-represented (p=0.006) in the TEN (25.9%) compared with the CON (17.1%) group. The TCT(AGGG) pseudohaplotypes constructed using these type XI collagen polymorphisms and the functional COL5A1 rs71746744 (-/AGGG) polymorphism were also significantly over-represented (p<0.001) in the TEN (25.2%) compared with the CON (9.1%) group. DISCUSSION: The genes encoding structural and functionally related type XI (COL11A1 and COL11A2) and type V (COL5A1) collagens interact with one another to collectively modulate the risk for AT. Although there are no immediate clinical applications, the results of this study provide additional evidence that interindividual variations in collagen fibril assembly might be an important molecular mechanism in the aetiology of chronic AT.

Application of an in silico approach identifies a genetic locus within ITGB2, and its interactions with HSPG2 and FGF9, to be associated with anterior cruciate ligament rupture risk.

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.

Genetic variants within the COL5A1 gene are associated with ligament injuries in physically active populations from Australia, South Africa, and Japan.

Previous small-scale studies have shown an association between the COL5A1 gene and anterior cruciate ligament (ACL) injury risk. In this larger study, the genotype and allele frequency distributions of the COL5A1 rs12722 C/T and rs10628678 AGGG/deletion (AGGG/-) indel variants were compared between participants: (i) with ACL injury in independent and combined cohorts from South-Africa (SA) and Australia (AUS) vs controls (CON), and (ii) with any ligament (ALL) or only ACL injury in a Japanese (JPN) cohort vs CON. Samples were collected from SA (235 cases; 232 controls), AUS (362 cases; 80 controls) and JPN (500 cases; 1,403 controls). Genomic DNA was extracted and genotyped. Distributions were compared, and inferred haplotype analyses performed. No independent associations were noted for rs12722 or rs10628678 when the combined SA + AUS cohort was analysed. However, the C-deletion (rs12722-rs10628678) inferred haplotype was under-represented (p = 0.040, OR = 0.15, CI = 0.04-0.56), while the T-deletion inferred haplotype was over-represented in the female SA + AUS ACL participants versus controls (p < 0.001, OR = 4.74, CI = 1.66-13.55). Additionally, the rs12722 C/C genotype was under-represented in JPN CON vs ACL (p = 0.039, OR = 0.52, 0.27-1.00), while the rs10628678 -/- genotype was associated with increased risk of any ligament injuries (p = 0.035, OR = 1.31, CI = 1.02-1.68) in the JPN cohort. Collectively, these results highlight that a region within the COL5A1 3'-UTR is associated with ligament injury risk. This must be evaluated in larger cohorts and its functional relevance to the structure and capacity of ligaments and joint biomechanics be explored.Highlights The COL5A1 T-deletion inferred haplotype (rs12722-rs10628678) was associated with an increased risk of ACL rupture in the combined SA and AUS female participants.The COL5A1 C-deletion inferred haplotype (rs12722-rs10628678) was associated with a decreased risk of ACL rupture in the combined SA and AUS female participants.The COL5A1 rs12722 C/C and rs10628678 -/- genotypes were associated with increased risk of ACL rupture and of ligament injuries in JPN, respectively.A region within the COL5A1 3'-UTR is associated with risk of ligament injury, including ACL rupture, and therefore the functional significance of this region on ligament capacity and joint biomechanics requires further exploration.

Polymorphisms in COMT and OPRM1 Collectively Contribute to Chronic Shoulder Pain and Disability in South African Breast Cancer Survivors'.

Chronic shoulder pain and disability is a common adverse effect experienced by >40% of breast cancer survivors (BCS). Pain management protocols for acute and chronic pain include the use of opioids and opioid derivatives. Furthermore, pain-modulating genes, such as COMT and OPRM1, have been linked to the aetiology of chronic pain. This study aimed to investigate the association between genetic variants of major pain modulator genes and chronic pain/disability in BCS. Assessment of pain, disability and combined (pain and disability) symptoms were determined using the Shoulder Pain and Disability Index (SPADI). Participants were grouped according to their scores such as no-low (<30%) and moderate-high (≥30%) groups of pain, disability and combined (pain and disability). Genotyping of the COMT rs6269 (A > G), rs4633 (C > T), rs4818 (C > G) and the functional rs4680(G > A) SNPs within the BCS (N = 252) cohort were conducted using TaqMan® SNP assays. Genotype, allele, haplotype, and allele-allele combination frequencies were evaluated. Statistical analysis was applied, with significance accepted at p < 0.05. The COMT rs4680:A/A genotype was significantly associated with moderate-high pain (p = 0.024, OR: 3.23, 95% CI: 1.33-7.81) and combined (pain and disability) (p = 0.015, OR: 3.81, 95% CI: 1.47-9.85). The rs4680:A allele was also significantly associated with moderate-high pain (p = 0.035, OR: 1.58, 95% CI: 1.03-2.43) and combined (pain and disability) (p = 0.017, OR: 1.71, 95% CI: 1.07-2.71). For the inferred COMT (rs6269 A > G-rs4680 G > A) haplotype analyses, the G-G (p = 0.026, OR: 0.67, 95% CI: 0.38-1.18) and A-A (p = 0.007, OR: 2.09, 95% CI: 0.89-4.88) haplotypes were significantly associated with reduced and increased likelihoods of reporting moderate-high pain, respectively. The inferred A-A (p = 0.003, OR: 2.18, 95% CI: 0.92-5.17) haplotype was also significantly associated with combined (pain and disability). Gene-gene interaction analyses further showed allele-allele combinations for COMT (rs4680 G > A)-OPRM1 (rs1799971 A > G) and COMT (rs4680 G > A)-OPRM1(rs540825 T > A) were associated with reporting pain and combined (pain and disability) symptoms, p < 0.05. The findings of this study suggest that COMT and OPRM1 SNPs play a role in the development of chronic shoulder pain/disability in BCS in a unique South African cohort from the Western Cape.

ABCB1 and OPRM1 single-nucleotide polymorphisms collectively modulate chronic shoulder pain and dysfunction in South African breast cancer survivors.

Background: Chronic shoulder pain/disability is a well-recognized side effect of treatment for breast cancer, with ∼40% of patients experiencing this, despite receiving pain management. To manage acute and chronic pain, several opioids are commonly prescribed. Pharmacogenomics have implicated genes within the opioid signaling pathway, including ABCB1 and OPRM1, to contribute to an individual's variable response to opioids. Aim: To evaluate ABCB1 (rs1045642 G>A, rs1128503 G>A) and OPRM1 (rs1799971 A>G, rs540825 T>A) single-nucleotide polymorphisms (SNPs) in chronic shoulder pain/disability in BCS. Materials & methods: TaqManTM assays were used to genotype ABCB1 and OPRM1 SNPs within the BCS (N = 252) cohort. The Shoulder Pain and Disability Index was used to evaluate pain and disability features associated with shoulder pathologies. Participants end scores for each feature (pain, disability and combined [pain and disability]) were categorized into no-low (>30%) and moderate-high (≥30%) scores. Statistical analysis was applied, and significance was accepted at p < 0.05. Results: Of participants, 27.0, 19.0 and 22.0% reported moderate-high pain, disability and combined (pain and disability) scores, respectively. ABCB1:rs1045642-(A/A) genotype was significantly associated with disability (p = 0.028: no-low [14.9%] vs mod-high [4.3%]) and combined (pain and disability) (p = 0.011: no-low [15.9%] vs mod-high [5.7%]). The ABCB1:rs1045642-(A) allele was significantly associated with disability (p = 0.015: no-low [37.9%] vs mod-high [23.9%]) and combined (pain and disability) (p = 0.003: no-low [38.5%] vs mod-high [23.6%]). The inferred ABCB1 (rs1045642 G>A - rs1128503 G>A): A-G (p = 0.029; odds ratio [OR]: 0.0; 95% CI: 0.0-0.0) and the OPRM1 (rs1799971 A>G - rs540825 T>A): G-T (p = 0.019; OR: 0.33; 95% CI: 0.14-0.75) haplotypes were associated with disability and pain, respectively. Gene-gene interactions showed the ABCB1 (rs1045642 G>A) - OPRM1 (rs540825 T>A) combinations, (A-T) (p = 0.019; OR: 0.62; 95% CI: 0.33-1.16) and (G-A) (p = 0.021; OR: 1.57; 95% CI: 0.30-3.10) were associated with disability. Conclusion: The study implicated ABCB1 with shoulder pain and disability; and haplotype analyses identified specific genetic intervals within ABCB1 and OPRM1 to associate with chronic shoulder pain and disability. Evidence suggests that potentially gene-gene interactions between ABCB1 and OPRM1 contribute to chronic shoulder pain and disability experienced in this SA cohort.

Tendon and Ligament Genetics: How Do They Contribute to Disease and Injury? A Narrative Review.

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.