Identification of chromosomal regions associated with cranial cruciate ligament rupture in a population of Newfoundlands

Wilke, Vicki L.; Zhang, Shu; Evans, Richard B.; Conzemius, Michael G.; Rothschild, Max F.

doi:10.2460/ajvr.70.8.1013

Cited by 27 publications

(23 citation statements)

References 13 publications

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“…However, the presence of stifle synovitis histologically increases the risk of subsequent contralateral CrCLR [10], although there is no evidence of a MHC class II immunogenetic association [38]. Non-contact CrCLR is a complex trait, with multiple genes contributing to development of the phenotype [39]. Heritability is estimated to be 0.27 in Newfoundlands, suggesting that extrinsic factors also have a substantial effect on expression of the phenotype [40].…”

Section: Discussionmentioning

confidence: 99%

“…Intrinsic factors include genetics, cruciate ligament matrix composition, stifle morphology, and body weight. Extrinsic factors include body condition, whether or not ovariohysterectomy or castration has been performed, and development of synovitis [4], [10], [39]–[45]. In the present study, we examined the effect of gender, breed, body weight, age, and TPA on risk of subsequent contralateral CrCLR in a large population of dogs.…”

Section: Discussionmentioning

confidence: 99%

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Contralateral Cruciate Survival in Dogs with Unilateral Non-Contact Cranial Cruciate Ligament Rupture

et al. 2011

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BackgroundNon-contact cranial cruciate ligament rupture (CrCLR) is an important cause of lameness in client-owned dogs and typically occurs without obvious injury. There is a high incidence of bilateral rupture at presentation or subsequent contralateral rupture in affected dogs. Although stifle synovitis increases risk of contralateral CrCLR, relatively little is known about risk factors for subsequent contralateral rupture, or whether therapeutic intervention may modify this risk.Methodology/Principal FindingsWe conducted a longitudinal study examining survival of the contralateral CrCL in client-owned dogs with unilateral CrCLR in a large baseline control population (n = 380), and a group of dogs that received disease-modifying therapy with arthroscopic lavage, intra-articular hyaluronic acid and oral doxycycline (n = 16), and were followed for one year. Follow-up in treated dogs included analysis of mobility, radiographic evaluation of stifle effusion and arthritis, and quantification of biomarkers of synovial inflammation. We found that median survival of the contralateral CrCL was 947 days. Increasing tibial plateau angle decreased contralateral ligament survival, whereas increasing age at diagnosis increased survival. Contralateral ligament survival was reduced in neutered dogs. Our disease-modifying therapy did not significantly influence contralateral ligament survival. Correlative analysis of clinical and biomarker variables with development of subsequent contralateral rupture revealed few significant results. However, increased expression of T lymphocyte-associated genes in the index unstable stifle at diagnosis was significantly related to development of subsequent non-contact contralateral CrCLR.ConclusionSubsequent contralateral CrCLR is common in client-owned dogs, with a median ligament survival time of 947 days. In this naturally occurring model of non-contact cruciate ligament rupture, cranial tibial translation is preceded by development of synovial inflammation. However, treatment with arthroscopic lavage, intra-articular hyaluronic acid and oral doxycycline does not significantly influence contralateral CrCL survival.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Contralateral Cruciate Survival in Dogs with Unilateral Non-Contact Cranial Cruciate Ligament Rupture

et al. 2011

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“…The authors reported a prevalence for CCL deficiency of 22%, and proposed a recessive mode of inheritance, with 51% penetrance. Four microsatellite markers located on 4 chromosomes were consequently associated with CCL deficiency in a subset of 90 Newfoundlands 15 . In spite of the particularly high prevalence and OR in that breed, only 27% of the phenotypic expression of CCLD in these dogs was attributable to genetics, whereas 73% was linked to environmental factors 14 .…”

Section: Influence Of Geneticsmentioning

confidence: 98%

A Review of the Pathogenesis of Canine Cranial Cruciate Ligament Disease as a Basis for Future Preventive Strategies

Griffon

2010

Veterinary Surgery

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Cranial cruciate ligament (CCL) deficiency is the leading cause of lameness of the canine stifle and has important consequences in terms of morbidity and cost associated with its management. In spite of this impact, development of preventive strategies remains in its infancy, largely because of gaps in our understanding of the complex and likely multifactorial origin of CCL deficiency. The purpose of this article is to provide a critical review of the literature related to the pathogenesis of CCL deficiency and place this evidence in the context of potential preventive measures. Trauma accounts for a minority of CCL ruptures in dogs, whereas progressive degeneration of the ligament has been attributed to a variety of factors that may be broadly classified as genetic, conformational, environmental, immune-mediated, and inflammatory. Genetic screening appears promising as a long-term option in selected breeds while immunomodulating therapies may be implemented in the nearer future to reduce the incidence of contralateral disease in dogs with unilateral CCL deficiency. Preventive modification of conformation factors may be applicable to most breeds predisposed to CCL deficiency but requires further investigations into the relative contribution of individual factors, as well as into the feasibility, and potential risks of large-scale implementation.

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“…Four putative QTL were described that underlie RCCL in this Newfoundland pedigree [16]. A GWAS conducted on these same Newfoundland dogs reported associations on CFA1, 10, and 33 [21], none of which overlapped with the loci previously reported by linkage analysis in the same pedigree [22]. However, single nucleotide polymorphisms (SNPs) in key genes involved in ligament strength, stability and extracellular matrix composition were associated with RCCL susceptibility across a single case and a single control from four different dog breeds [21].…”

Section: Introductionmentioning

confidence: 95%

A novel iterative mixed model to remap three complex orthopedic traits in dogs

et al. 2017

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Hip dysplasia (HD), elbow dysplasia (ED), and rupture of the cranial (anterior) cruciate ligament (RCCL) are the most common complex orthopedic traits of dogs and all result in debilitating osteoarthritis. We reanalyzed previously reported data: the Norberg angle (a quantitative measure of HD) in 921 dogs, ED in 113 cases and 633 controls, and RCCL in 271 cases and 399 controls and their genotypes at ~185,000 single nucleotide polymorphisms. A novel fixed and random model with a circulating probability unification (FarmCPU) function, with marker-based principal components and a kinship matrix to correct for population stratification, was used. A Bonferroni correction at p<0.01 resulted in a P< 6.96 ×10−8. Six loci were identified; three for HD and three for RCCL. An associated locus at CFA28:34,369,342 for HD was described previously in the same dogs using a conventional mixed model. No loci were identified for RCCL in the previous report but the two loci for ED in the previous report did not reach genome-wide significance using the FarmCPU model. These results were supported by simulation which demonstrated that the FarmCPU held no power advantage over the linear mixed model for the ED sample but provided additional power for the HD and RCCL samples. Candidate genes for HD and RCCL are discussed. When using FarmCPU software, we recommend a resampling test, that a positive control be used to determine the optimum pseudo quantitative trait nucleotide-based covariate structure of the model, and a negative control be used consisting of permutation testing and the identical resampling test as for the non-permuted phenotypes.

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Identification of chromosomal regions associated with cranial cruciate ligament rupture in a population of Newfoundlands

Cited by 27 publications

References 13 publications

Contralateral Cruciate Survival in Dogs with Unilateral Non-Contact Cranial Cruciate Ligament Rupture

Contralateral Cruciate Survival in Dogs with Unilateral Non-Contact Cranial Cruciate Ligament Rupture

A Review of the Pathogenesis of Canine Cranial Cruciate Ligament Disease as a Basis for Future Preventive Strategies

A novel iterative mixed model to remap three complex orthopedic traits in dogs

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