Abstract
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.
Highlights
Musculoskeletal soft tissue injury is an encompassing term used to describe pathologies affecting tendons, ligaments and skeletal muscles [1]
The CON and TEN samples in the Achilles tendinopathy sample group were previously genotyped for the TNC rs2104772 variant and the results presented by Saunders et al 2012 [26]
With respect to the genes previously associated with Achilles tendinopathy using a candidate gene approach, 338 variants were identified, 19 demonstrating allele frequency differences equal to or above the 30% threshold (Fig 2)
Summary
Musculoskeletal soft tissue injury is an encompassing term used to describe pathologies affecting tendons, ligaments and skeletal muscles [1]. These phenotypes commonly present at clinical practices, with patients reporting impaired sporting performance and decreased functional capacity [1]. The underlying biological origin of these injuries is complex and still highly debated. It is interesting to note that tendons and ligaments are anatomically distinct structures with different primary functions, they are similar in molecular composition and share several morphological features [8]. It is not surprising that there are similarities (shared) and differences (unique) in the loci implicated in these clinically distinct musculoskeletal injuries [2]
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