Polymorphisms within theCOL5A1gene and regulators of the extracellular matrix modify the risk of Achilles tendon pathology in a British case-control study

Abstract

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-1β, 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.

The Apoptosis Pathway and CASP8 Variants Conferring Risk for Acute and Overuse Musculoskeletal Injuries

“…Similar and contrasting findings were noted in the associations of the CASP8 inferred haplotypes across the three different musculoskeletal injury phenotypes. The del‐C inferred haplotype (rs3834129–rs1045485) found to be associated with decreased risk of non‐contact ACL ruptures aligns with (i) the del‐C inferred haplotype associated with a decreased risk of AT in a combined South Africa and Australian study, and (ii) with the direction of the alternate alleles in the ins‐G inferred haplotype associated with an increased risk of AT in a British study . In contrast, however, the del‐G inferred haplotype was previously associated with an increased risk for both AT and ACL ruptures .…”

“…). The rs3834129 (ins/del) and rs1045485 (G/C) variants selected based on their previous associations with AT and ACL ruptures . The rs13113 (T/A) variant was selected for investigation via a targeted whole exome sequencing approach …”

“…It is also evident from the combined haplotype results across the three independent cohort studies, as well as previously published studies, that there are genomic regions of interest in the CASP8 gene that require further investigation in injury susceptibility model for musculoskeletal phenotypes. [21][22][23]43,44 JOURNAL OF ORTHOPAEDIC RESEARCH ® MARCH 2020…”

“…CASP8 is encoded by the CASP8 gene, which spans a ~30 kb region on human chromosome 2q33‐34 . Variants within the CASP8 gene, rs3834129 (ins/del) and rs1045485 (G/C) have been implicated in a number of degenerative conditions, including musculoskeletal soft tissue injuries, such as Achilles tendinopathy (AT) and ACL ruptures …”

“…19,20 CASP8 is encoded by the CASP8 gene, which spans ã 30 kb region on human chromosome 2q33-34. 21 Variants within the CASP8 gene, rs3834129 (ins/del) and rs1045485 (G/C) have been implicated in a number of degenerative conditions, including musculoskeletal soft tissue injuries, such as Achilles tendinopathy (AT) 22,23 and ACL ruptures. 24 The primary aim of this study was to investigate previously implicated DNA sequence variants within the CASP8 gene, rs3834129 (ins/del) and rs1045485 (G/C) and explore additional CASP8 gene variants with risk of musculoskeletal injury phenotypes, including rotator cuff tendinopathy (RCT), ACL ruptures and carpal tunnel syndrome (CTS).…”