Browsing by Author "Saunders, Colleen J."

Now showing 1 - 7 of 7
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    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
    (Taylor and Francis Group, 2023) Dlamini, Senanile B.; Saunders, Colleen J.; Laguette, Mary-Jessica N.
    We developed a Biomedical Knowledge Graph model that is phenotype and biological functionaware 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.
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    Application of anin silicoapproach identifies a genetic locus withinITGB2,and itsinteractions withHSPG2 and FGF9,to be associated with anterior cruciateligament rupture risk
    (Taylor and Francis Group, 2023) Dlamini, Senanile B.; Saunders, Colleen J.; Gamieldien, Junaid
    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. Allknown human genes were assessed through the model to identify potential new risk genes foranterior cruciate ligament (ACL) ruptures and Achilles tendinopathy (AT). Genes were prioritisedand 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 controlindividuals (CON). After genefiltering, 3376 genes, including 411 genes identified throughprevious 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/TandFGF9:rs2274296C/T. The rs2230528 CC genotype was over-represented in the CON groupcompared to ACL-R (p< 0.001) and ACL-NON (p< 0.001) and the TT genotype and T allele wereover-represented in the ACL-R group and ACL-NON compared to CON (p< 0.001) group. Severalsignificant differences in distributions were noted for the gene-gene interactions: (HSPG2:rs2291826, rs2291827 andITGB2:rs2230528) and (ITGB2:rs2230528 andFGF9:rs2297429).
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    Defining the molecular signatures of Achilles tendinopathy and anterior cruciate ligament ruptures: A whole-exome sequencing approach
    (Public Library of Science, 2018) Gibbon, Andrea; Saunders, Colleen J.; Collins, Malcolm; Gamieldien, Junaid; September, Alison V.
    Musculoskeletal soft tissue injuries are complex phenotypes with genetics being one of many proposed risk factors. Case-control association studies using the candidate gene approach have predominately been used to identify risk loci for these injuries. However, the ability to identify all risk conferring variants using this approach alone is unlikely. Therefore, this study aimed to further define the genetic profile of these injuries using an integrated omics approach involving whole exome sequencing and a customised analyses pipeline. The exomes of ten exemplar asymptomatic controls and ten exemplar cases with Achilles tendinopathy were individually sequenced using a platform that included the coverage of the untranslated regions and miRBase miRNA genes. Approximately 200 000 variants were identified in the sequenced samples. Previous research was used to guide a targeted analysis of the genes encoding the tenascin-C (TNC) glycoprotein and the α1 chain of type XXVII collagen (COL27A1) located on chromosome 9. Selection of variants within these genes were; however, not predetermined but based on a tiered filtering strategy. Four variants in TNC (rs1061494, rs1138545, rs2104772 and rs1061495) and three variants in the upstream COL27A1 gene (rs2567706, rs2241671 and rs2567705) were genotyped in larger Achilles tendinopathy and anterior cruciate ligament (ACL) rupture sample groups. The CC genotype of TNC rs1061494 (C/T) was associated with the risk of Achilles tendinopathy (p = 0.018, OR: 2.5 95% CI: 1.2–5.1). Furthermore, the AA genotype of the TNC rs2104772 (A/T) variant was significantly associated with ACL ruptures in the female subgroup (p = 0.035, OR: 2.3 95% CI: 1.1–5.5). An inferred haplotype in the TNC gene was also associated with the risk of Achilles tendinopathy. These results provide a proof of concept for the use of a customised pipeline for the exploration of a larger genomic dataset. This approach, using previous research to guide a targeted analysis of the data has generated new genetic signatures in the biology of musculoskeletal soft tissue injuries.
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    Designing a course model for distance-based online bioinformatics training in Africa: the H3ABioNet experience
    (Public Library of Science, 2017) Gurwitz, Kim T.; Aron, Shaun; Entfellner, Jean-Baka Domelevo; Saunders, Colleen J.; Cloete, Ruben
    Africa is not unique in its need for basic bioinformatics training for individuals from a diverse range of academic backgrounds. However, particular logistical challenges in Africa, most notably access to bioinformatics expertise and internet stability, must be addressed in order to meet this need on the continent. H3ABioNet (www.h3abionet.org), the Pan African Bioinformatics Network for H3Africa, has therefore developed an innovative, free-of-charge "Introduction to Bioinformatics" course, taking these challenges into account as part of its educational efforts to provide on-site training and develop local expertise inside its network. A multiple-delivery±mode learning model was selected for this 3-month course in order to increase access to (mostly) African, expert bioinformatics trainers. The content of the course was developed to include a range of fundamental bioinformatics topics at the introductory level. For the first iteration of the course (2016), classrooms with a total of 364 enrolled participants were hosted at 20 institutions across 10 African countries. To ensure that classroom success did not depend on stable internet, trainers pre-recorded their lectures, and classrooms downloaded and watched these locally during biweekly contact sessions. The trainers were available via video conferencing to take questions during contact sessions, as well as via online "question and discussion" forums outside of contact session time. This learning model, developed for a resource-limited setting, could easily be adapted to other settings.
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    Exploring new genetic variants within col5a1 intron 4‐exon 5 region and tgf‐β family with risk of anterior cruciate ligament ruptures
    (Wiley, 2020) Laguette, Mary‐Jessica N.; Barrow, Kelly; Saunders, Colleen J.
    Variants within genes encoding structural and regulatory elements of ligaments have been associated with musculoskeletal soft tissue injury risk. The role of intron 4‐exon 5 variants within the α1 chain of type V collagen (COL5A1) gene and genes of the transforming growth factor‐β (TGF‐β) family, TGFBR3 and TGFBI, was investigated on the risk of anterior cruciate ligament (ACL) ruptures. A case‐control genetic association study was performed on 210 control (CON) and 249 participants with surgically diagnosed ruptures (ACL), of which 147 reported a noncontact mechanism of injury (NON). Whole‐exome sequencing data were used to prioritize variants of potential functional relevance.
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    Semantic interrogation of a multi knowledge domain ontological model of tendinopathy identifies four strong candidate risk genes
    (Nature Research, 2016) Saunders, Colleen J.; Dashti, Mahjoubeh Jalali Sefid; Gamieldien, Junaid
    Tendinopathy is a multifactorial syndrome characterised by tendon pain and thickening, and impaired performance during activity. Candidate gene association studies have identified genetic factors that contribute to intrinsic risk of developing tendinopathy upon exposure to extrinsic factors. Bioinformatics approaches that data-mine existing knowledge for biological relationships may assist with the identification of candidate genes. The aim of this study was to data-mine functional annotation of human genes and identify candidate genes by ontology-seeded queries capturing the features of tendinopathy. Our BioOntological Relationship Graph database (BORG) integrates multiple sources of genomic and biomedical knowledge into an on-disk semantic network where human genes and their orthologs in mouse and rat are central concepts mapped to ontology terms. The BORG was used to screen all human genes for potential links to tendinopathy. Following further prioritisation, four strong candidate genes (COL11A2, ELN, ITGB3, LOX) were identified. These genes are differentially expressed in tendinopathy, functionally linked to features of tendinopathy and previously implicated in other connective tissue diseases. In conclusion, cross-domain semantic integration of multiple sources of biomedical knowledge, and interrogation of phenotypes and gene functions associated with disease, may significantly increase the probability of identifying strong and unobvious candidate genes in genetic association studies.
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    Variants within the COMP and THBS2 genes are not associated with Achilles tendinopathy in a case-control study of South African and Australian populations
    (Taylor & Francis, 2013) Saunders, Colleen J.; Van Der Merwe, Lize; Cook, Jill; Handley, Christopher J.; Collins, Malcolm; September, Alison V.
    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.