Defining the molecular signatures of Achilles tendinopathy and anterior cruciate ligament ruptures: A whole-exome sequencing approach

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dc.contributor.authorGibbon, Andrea
dc.contributor.authorSaunders, Colleen J.
dc.contributor.authorCollins, Malcolm
dc.contributor.authorGamieldien, Junaid
dc.contributor.authorSeptember, Alison V.
dc.date.accessioned2018-11-05T07:05:20Z
dc.date.available2018-11-05T07:05:20Z
dc.date.issued2018
dc.description.abstractMusculoskeletal 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.en_US
dc.description.accreditationISI
dc.identifier.citationGibbon, A. et al. (2018). Defining the molecular signatures of Achilles tendinopathy and anterior cruciate ligament ruptures: A whole-exome sequencing approach. PLoS ONE, 13(10): e0205860.en_US
dc.identifier.issn1932-6203
dc.identifier.urihttps://doi.org/10.1371/journal. pone.0205860
dc.identifier.urihttp://hdl.handle.net/10566/4179
dc.language.isoenen_US
dc.privacy.showsubmitterFALSE
dc.publisherPublic Library of Scienceen_US
dc.rights© 2018 Gibbon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.status.ispeerreviewedTRUE
dc.subjectMusculoskeletal soft tissue injuriesen_US
dc.subjectComplex phenotypesen_US
dc.subjectGenetic profileen_US
dc.subjectmiRBase miRNA genesen_US
dc.titleDefining the molecular signatures of Achilles tendinopathy and anterior cruciate ligament ruptures: A whole-exome sequencing approachen_US
dc.typeArticleen_US

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