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These injuries are multifactorial in nature, with several identified intrinsic and extrinsic risk factors. Previous studies have implicated specific sequence variants within genes encoding structural and regulatory components of the extracellular matrix of tendons and\/ligaments to predispose individuals to these injuries. An example, includes the association of sequence variants within the apoptotic regulatory gene, <jats:italic>caspase\u20108<\/jats:italic> (<jats:italic>CASP8<\/jats:italic>) with other musculoskeletal injury phenotypes, such as Achilles tendinopathy. The primary aim of this study was, therefore, to investigate previously implicated DNA sequence variants within <jats:italic>CASP8<\/jats:italic>: rs3834129 (ins\/del) and rs1045485 (G\/C), and the rs13113 (T\/A) identified using a whole exome sequencing approach, with risk of musculoskeletal injury phenotypes (RCT, ACL ruptures, and CTS) in three independent studies. In addition, the aim was to implicate a <jats:italic>CASP8<\/jats:italic> genomic interval in the modulation of risk of RCT, ACL ruptures, or CTS. It was found that the AA genotype of <jats:italic>CASP8<\/jats:italic> rs13113 (T\/A) was independently associated with increased risk for CTS. In addition, it was found that the del\u2010C haplotype (rs3834129\u2013rs1045485) was significantly associated with non\u2010contact ACL ruptures, which is in alignment with previous research findings. Collectively, the results of this study implicate the apoptosis pathway as biologically significant in the underlying pathogenesis of musculoskeletal injury phenotypes. These findings should be repeated in larger sample cohorts and across different populations. \u00a9 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. 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