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Analysis of copy number variation in dogs implicates genomic structural variation in the development of anterior cruciate ligament rupture.

ABSTRACT: Anterior cruciate ligament (ACL) rupture is an important condition of the human knee. Second ruptures are common and societal costs are substantial. Canine cranial cruciate ligament (CCL) rupture closely models the human disease. CCL rupture is common in the Labrador Retriever (5.79% prevalence), ~100-fold more prevalent than in humans. Labrador Retriever CCL rupture is a polygenic complex disease, based on genome-wide association study (GWAS) of single nucleotide polymorphism (SNP) markers. Dissection of genetic variation in complex traits can be enhanced by studying structural variation, including copy number variants (CNVs). Dogs are an ideal model for CNV research because of reduced genetic variability within breeds and extensive phenotypic diversity across breeds. We studied the genetic etiology of CCL rupture by association analysis of CNV regions (CNVRs) using 110 case and 164 control Labrador Retrievers. CNVs were called from SNPs using three different programs (PennCNV, CNVPartition, and QuantiSNP). After quality control, CNV calls were combined to create CNVRs using ParseCNV and an association analysis was performed. We found no strong effect CNVRs but found 46 small effect (max(T) permutation P<0.05) CCL rupture associated CNVRs in 22 autosomes; 25 were deletions and 21 were duplications. Of the 46 CCL rupture associated CNVRs, we identified 39 unique regions. Thirty four were identified by a single calling algorithm, 3 were identified by two calling algorithms, and 2 were identified by all three algorithms. For 42 of the associated CNVRs, frequency in the population was <10% while 4 occurred at a frequency in the population ranging from 10-25%. Average CNVR length was 198,872bp and CNVRs covered 0.11 to 0.15% of the genome. All CNVRs were associated with case status. CNVRs did not overlap previous canine CCL rupture risk loci identified by GWAS. Associated CNVRs contained 152 annotated genes; 12 CNVRs did not have genes mapped to CanFam3.1. Using pathway analysis, a cluster of 19 homeobox domain transcript regulator genes was associated with CCL rupture (P = 6.6E-13). This gene cluster influences cranial-caudal body pattern formation during embryonic limb development. Clustered genes were found in 3 CNVRs on chromosome 14 (HoxA), 28 (NKX6-2), and 36 (HoxD). When analysis was limited to deletion CNVRs, the association was strengthened (P = 8.7E-16). This study suggests a component of the polygenic risk of CCL rupture in Labrador Retrievers is associated with small effect CNVs and may include aspects of stifle morphology regulated by homeobox domain transcript regulator genes.

SUBMITTER: Binversie EE

PROVIDER: S-EPMC7774950 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Analysis of copy number variation in dogs implicates genomic structural variation in the development of anterior cruciate ligament rupture.

Binversie Emily E EE Baker Lauren A LA Engelman Corinne D CD Hao Zhengling Z Moran John J JJ Piazza Alexander M AM Sample Susannah J SJ Muir Peter P

PloS one 20201231 12

Anterior cruciate ligament (ACL) rupture is an important condition of the human knee. Second ruptures are common and societal costs are substantial. Canine cranial cruciate ligament (CCL) rupture closely models the human disease. CCL rupture is common in the Labrador Retriever (5.79% prevalence), ~100-fold more prevalent than in humans. Labrador Retriever CCL rupture is a polygenic complex disease, based on genome-wide association study (GWAS) of single nucleotide polymorphism (SNP) markers. Dis ...[more]

PMID: 33382735

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Project description:BackgroundAnterior cruciate ligament (ACL) graft rupture occurs at a high rate, especially in young athletes. The geometries of the tibial plateau and femoral intercondylar notch are risk factors for first-time ACL injury; however, little is known about the relationship between these geometries and risk of ACL graft rupture.HypothesisThe geometric risk factors for noncontact graft rupture are similar to those previously identified for first-time noncontact ACL injury, and sex-specific differences exist.Study designCase-control study; Level of evidence, 3.MethodsEleven subjects who suffered a noncontact ACL graft rupture and 44 subjects who underwent ACL reconstruction but did not experience graft rupture were included in the study. Using magnetic resonance imaging, the geometries of the tibial plateau subchondral bone, articular cartilage, meniscus, tibial spines, and femoral notch were measured. Risk factors associated with ACL graft rupture were identified using Cox regression.ResultsThe following were associated with increased risk of ACL graft injury in males: increased posterior-inferior-directed slope of the articular cartilage in the lateral tibial plateau measured at 2 locations (hazard ratio [HR] = 1.50, P = .029; HR = 1.39, P = .006), increased volume (HR = 1.45, P = .01) and anteroposterior length (HR = 1.34, P = .0023) of the medial tibial spine, and increased length (HR = 1.18, P = .0005) and mediolateral width (HR = 2.19, P = .0004) of the lateral tibial spine. In females, the following were associated with increased risk of injury: decreased volume (HR = 0.45, P = .02) and height (HR = 0.46, P = .02) of the medial tibial spine, decreased slope of the lateral tibial subchondral bone (HR = 0.72, P = .01), decreased height of the posterior horn of the medial meniscus (HR = 0.09, P = .001), and decreased intercondylar notch width at the anterior attachment of the ACL (HR = 0.72, P = .02).ConclusionThe geometric risk factors for ACL graft rupture are different for males and females. For females, a decreased femoral intercondylar notch width and a decreased height of the posterior medial meniscus were risk factors for ACL graft rupture that have also been found to be risk factors for first-time injury. There were no risk factors in common between ACL graft injury and first-time ACL injury for males.

Project description:Cranial cruciate ligament rupture (CR) is a degenerative condition in dogs that typically has a non-contact mechanism. Subsequent contralateral rupture often develops in dogs with unilateral CR. Synovitis severity is an important factor that promotes ligament degradation. Consequently, we wished to evaluate the utility of arthroscopy for assessment of stifle synovitis in dogs with CR. Herein, we report results of a prospective study of 27 dogs with unilateral CR and bilateral radiographic osteoarthritis. Arthroscopic images and synovial biopsies from the lateral and medial joint pouches were obtained bilaterally and graded for synovial hypertrophy, vascularity, and synovitis. Synovial tartrate-resistant acid phosphatase-positive (TRAP+) macrophages, CD3(+) T lymphocytes, Factor VIII+ blood vessels, and synovial intima thickness were quantified histologically and related to arthroscopic observations. Risk of subsequent contralateral CR was examined using survival analysis. We found that arthroscopic scores were increased in the index stifle, compared with the contralateral stifle (p<0.05). Numbers of CD3+ T lymphocytes (SR = 0.50, p<0.05) and TRAP+ cells in joint pouches (SR = 0.59, p<0.01) were correlated between joint pairs. Arthroscopic grading of vascularity and synovitis was correlated with number density of Factor VIII+ vessels (SR>0.34, p<0.05). Arthroscopic grading of villus hypertrophy correlated with numbers of CD3(+) T lymphocytes (SR = 0.34, p<0.05). Synovial intima thickness was correlated with arthroscopic hypertrophy, vascularity, and synovitis (SR>0.31, p<0.05). Strong intra-observer and moderate inter-observer agreement for arthroscopic scoring was found. Dog age and arthroscopic vascularity significantly influenced risk of contralateral CR over time. We conclude that arthroscopic grading of synovitis is a precise tool that correlates with histologic synovitis. Arthroscopy is useful for assessment of stifle synovitis in client-owned dogs, and could be used in longitudinal clinical trials to monitor synovial responses to disease-modifying therapy.

Project description:BackgroundCranial cruciate ligament rupture (CCLR) is one of the most common causes of pelvic limb lameness in dogs. Risk factors for CCLR include breed (especially large and giant breeds), body weight, gender and spay/neuter status, and age. Few studies have evaluated physical activity and fitness indicators, however, as risk factors for disease. This study used an online questionnaire distributed primarily via social media to assess risk factors for CCLR in dogs actively engaged in agility training or competition to determine demographic and physical activity factors associated with rupture.ResultsData from 260 dogs with CCLR were compared to similar data from 1006 dogs without CCLR. All dogs were actively training or competing in agility at the time of CCLR or the time of data submission, respectively. Physical characteristics associated with increased risk of CCLR included younger age, spayed female sex, greater body weight, and greater weight to height ratio. Agility activities associated with increased odds ratios included competition in events sponsored by the North American Dog Agility Council (NADAC), competing at novice and intermediate levels, and competing in fewer than 10 events/year. Odds ratios were lower in dogs that competed in events sponsored by United Kingdom Agility International (UKI). Other activities associated with increased odds ratio for CCLR included involvement in flyball activities and short walks or runs over hilly or flat terrain on a weekly basis. Activities associated with decreased odds ratio included involvement in dock diving, barn hunt, nosework, or lure coursing/racing activities and participation in core balance and strength exercises at least weekly.ConclusionsThese results are consistent with previous studies demonstrating that body weight and spay/neuter status are risk factors for CCLR in dogs. This is the first report to demonstrate that risk of CCLR in agility dogs is decreased in dogs that engage in regular core strengthening exercises, compete more frequently, compete at higher levels, and compete in more athletically challenging venues.

Project description:CONTEXT:Manual perturbation training improves knee functional performance and mitigates abnormal gait in patients with anterior cruciate ligament (ACL) rupture. However, manual perturbation training is time- and labor-intensive for therapists. OBJECTIVE:To investigate whether perturbation training administered using a mechanical device can provide effects similar to manual training on clinical measures and knee biomechanics after ACL rupture. DESIGN:Prospective cohort (therapeutic) study. A 2?×?2 analysis of variance was used for statistical analysis. SETTING:A clinical and biomechanical laboratory. PATIENTS:Eighteen level I/II patients with acute ACL ruptures participated in this preliminary study. INTERVENTION:Nine patients received mechanical perturbation training on an automated mechanical device (mechanical group), and 9 patients received manual perturbation training (manual group). OUTCOME MEASURES:Patients completed performance-based testing (quadriceps strength and single-legged hop tests), patient-reported questionnaires (Knee Outcome Survey-Activities of Daily Living Scale, Global Rating Score, and International Knee Documentation Committee 2000), and 3-dimensional gait analysis before (pretesting) and after (posttesting) training. RESULTS:There was no significant group-by-time interaction found for all measures (P???.18). Main effects of time were found for International Knee Documentation Committee 2000 (pretesting: 69.10 [10.95], posttesting: 75.14 [7.19]), knee excursion during weight-acceptance (pretesting: 16.01° [3.99°]; posttesting: 17.28° [3.99°]) and midstance (pretesting: 14.78° [4.13°]; posttesting: 16.92° [4.53°]) and external knee-flexion moment (pretesting: 0.43 [0.11] N m/kg/m; posttesting: 0.48 [0.11] N m/kg/m) (P???.04). After accounting for pretesting groups' differences, the mechanical group scored significantly higher on triple hops (mechanical: 96.73% [6.65%]; manual: 84.97% [6.83%]) and 6-m timed hops (mechanical: 102.07% [9.50%]; manual: 91.21 [9.42%]) (P???.047) compared with manual group. CONCLUSION:The clinical significance of this study is the mechanical perturbation training produced effects similar to manual training, with both training methods were equally effective at improving patients' perception of knee function and increasing knee excursion and external flexion moment during walking after acute ACL rupture. Mechanical perturbation training is a potential treatment to improve patients' functional and biomechanical outcomes after ACL rupture.

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Analysis of copy number variation in dogs implicates genomic structural variation in the development of anterior cruciate ligament rupture.

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Analysis of copy number variation in dogs implicates genomic structural variation in the development of anterior cruciate ligament rupture.

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