Exploring new genetic variants within col5a1 intron 4‐exon 5 region and tgf‐β family with risk of anterior cruciate ligament ruptures

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

Epigenetic regulation and musculoskeletal injuries

Musculoskeletal injuries have a considerable socio-economic impact and are increasing in prevalence. Previous work has identified several intrinsic and extrinsic risk factors contributing to injury susceptibility. Recent work has identified a role for epigenetics as a contributing mechanism to the susceptibility of musculoskeletal soft tissue injuries. The current chapter focuses on new development in the epigenetics arena towards understanding the risk of musculoskeletal soft tissue injuries. Using case-control association studies, differential DNA methylation and miRNA profiles were observed in the context of patellar tendinopathy, rotator cuff tendon tears, Achilles tendon injuries, and anterior cruciate ligament ruptures. Moreover, clinical and ethical implications of epigenetic research and testing remain a central theme and were discussed. The recent development in this field suggests that it is plausible that epigenetic modifications may modulate extracellular matrix proteins’ function and/or expression, thereby contributing to musculoskeletal soft tissue injuries.</p

Investigation of multiple populations highlight VEGFA polymorphisms to modulate anterior cruciate ligament injury

Polymorphisms in VEGFA and KDR encoding proteins have been associated with anterior cruciate ligament (ACL) injury risk. We leveraged a collective sample from Sweden, Poland, and Australia to investigate the association of functional polymorphisms in VEGFA and KDR with susceptibility to ACL injury risk. Using a case–control genetic association approach, polymorphisms in VEGFA and KDR were genotyped and haplotypes inferred from 765 controls, and 912 cases clinically diagnosed with ACL rupture. For VEGFA, there was a significant overrepresentation of the rs2010963 CC genotype (p = 0.0001, false discovery rate [FDR]: p = 0.001, odds ratio [OR]: 2.16, 95% confidence interval [CI]: 1.47–3.19) in the combined ACL group (18%) compared to the combined control group (11%). The VEGFA (rs699947 C/A, rs1570360 G/A, rs2010963 G/C) A-A-G haplotype was significantly (p = 0.010, OR: 0.85, 95% CI: 0.69–1.05) underrepresented in the combined ACL group (23%) compared to the combined control group (28%). In addition, the A-G-G construct was significantly (p = 0.036, OR: 0.81, 95% CI: 0.64–1.02) underrepresented in the combined ACL group (12%) compared to the combined CON group (16%). Our findings support the association of the VEGFA rs2010963 CC genotype with increased risk and (ii) the VEGFA A-A-G haplotype with a reduced risk, and are in alignment with the a priori hypothesis. Collectively identifying a genetic interval within VEGFA to be implicated in ACL risk modulation and highlight further the importance of vascular regulation in ligament biology