Genetic basis of cranial cruciate ligament rupture (CCLR) in dogs

Abstract

Cranial Cruciate Ligament rupture (CCLR) is one of the most common forms of lameness in dogs and is analogous to rupture of the anterior cruciate ligament in humans, for which it can serve as a model. As there is a strong breed-related predisposition to CCLR in dogs, a study was undertaken to consider putative genetic components in susceptible dog breeds. A candidate gene, single nucleotide polymorphism (SNP) genotyping approach using MALDI-TOF mass spectrometry (Sequenom Ltd) was designed to investigate several CCLR-susceptible dog breeds and identify CCLR-associated genes/gene regions that may confer susceptibility or resistance. A meta-analysis was performed using the breed case/control candidate gene data to identify SNP associations that were common to the whole cohort of susceptible dogs. We identified SNPs in key genes involved in ligament strength, stability and extracellular matrix formation (COL5A1, COL5A2, COL1A1, COL3A1, COL11A1, COL24A1, FBN1, LOX, LTBP2) which were significantly associated with CCLR susceptibility across the dog breeds used in this study. These SNPs could have an involvement in CCLR due to a detrimental effect on ligament structure and strength. This is the first published candidate gene study that has revealed significant genetic associations with canine CCLR.

ACL Research Retreat VII: An Update on Anterior Cruciate Ligament Injury Risk Factor Identification, Screening, and Prevention

“…183 Using a genome-wide association study design, the same investigators 184 have also identified 3 main chromosomal regions, which include variants within neurologic pathway genes, associated with canine cranial cruciate ligament rupture.…”

Breed, gender, age and reproductive status in relation to the predisposition for cranial cruciate ligament rupture in 117 dogs treated by a single surgeon (2010 - 2015) - a short communication

“…Mixed breed dogs, as the most common breed in this study had CCL rupture at an average age of 7.7 years. Dogs aged 5 years and older had 2.5 times the odds of CCL rupture compared with dogs aged less than 5 years, P<0.01. there is a strong breed-related predisposition to CCL rupture in dogs (BaIrD, 2014). West Highland White Terriers, Yorkshire Terriers and Rottweilers had a significantly higher prevalence of CCLR, and Rottweilers had five times greater incidence compared with other pure breeds, with females twice as likely to suffer CCLr compared to males (aDaMS et al, 2011).…”

“…Breed predisposition has been detected in Neapolitan Mastiff, akita, Saint Bernard, rottweiler, Mastiff, Newfoundland, Chesapeake Bay retriever, Labrador retriever, and american Staffordshire terrier (COrr, 2009) breeds, while the Greyhound has a dramatically reduced frequency of this disorder, supporting the heritable basis of the CCL rupture trait (BaIrD et al, 2014). Increased incidence has also been detected for neutered males and females with a slight majority of females, as well as for older dogs with an average age of 7 years in an earlier study (haraSeN, 2003).…”

Biological variation in musculoskeletal injuries: current knowledge, future research and practical implications

“…These genes include, among others, COL5A1, COL1A1, COL3A1, COL11A1 and FBN1. 21 One GWAS has identified three main chromosomal regions associated with CCLR on chromosomes 1, 3 and 33. Interestingly, the results of this study implicate the involvement of neurological pathways in susceptibility to CCLR 22.…”

“…1),2–8 Achilles tendon injuries (reviewed in refs. 9 and 10),4 11 12 lateral epicondylitis,13 rotator cuff injuries14–16 and carpal tunnel syndrome17–19 in humans, as well as, equine superficial digital flexor tendinopathy20 and canine cranial cruciate ligament rupture (CCLR) 21 22…”