Mário Ginja, Ana Rita Gaspar, Catarina Ginja, 2, and 3 are from the Department of Veterinary Sciences-CITAB at the University of Trás-os-Montes and Alto Douro in Vila Real, Portugal, the Center for Ecology, Evolution, and Environmental Change at the University of Lisboa, and the Center for Research on Biodiversity and Genetic Resources at the University of Porto in Vairo, Portugal, respectively. This characteristic, which was first noted in dogs in 1935, causes crippling secondary hip osteoarthritis. The diagnosis is verified radiographically by looking for incongruence, degenerative joint disease, and/or passive hip joint laxity symptoms. Because there is no perfect medical or surgical cure, prevention based on carefully regulated breeding is the best course of action. Radiation exposure while the dog is under general anesthesia or deep sedation is required for the definitive diagnosis of CHD based on radiographic examination, but this procedure hides the dog’s underlying genetic makeup. Environmental factors affect how CHD manifests in phenotypes, and dogs with normal phenotypes may carry certain mutations and pass these genes on to their progeny. While effective when strictly followed, programs that select dogs for breeding based on their better individual phenotypes are still inferior to those that select dogs based on an estimation of breeding values. The genetic basis of CHD is being investigated molecularly, but progress has been slow. In the future, it would be advised to base the method for enhancing hip quality in controlled breeding schemes on the estimation of the genomic breeding value, which will allow for higher selection pressure. Since 2012, a commercial DNA test for Labrador Retrievers has been available that uses blood samples and predicts the likelihood that CHD will develop. However, we are still waiting for proof that this test lowers the incidence or severity of CHD. Keywords: canine hip dysplasia, phenotype, breeding stock, GWAS, screening, diagnosis.
Canine hip dysplasia (CHD) is the most prevalent inherited polygenic orthopedic trait, with environmental factors influencing the phenotype. 1 This trait, which causes crippling secondary hip osteoarthritis in dogs, was first identified in the USA in 1935. 2 Heritability estimates for CHD vary from 0. 1 to 0. 83,3,4 because of the various pedigrees, heritability calculation techniques, and hip phenotypes examined. Large and giant dog breeds are more likely to have CHD, which frequently has mild or no clinical symptoms. 1,6 But for some dogs, the clinical symptoms can be severe and difficult to treat medically, necessitating forceful and costly surgical procedures. 1,7 If distinctive radiographic signs are visible on a standard or stressed ventrodorsal view of the pelvis, occurring along a gradual scale from nearly normal to severely affected, the diagnosis of CHD is made. This is a crucial aspect of CHD because the choice of breeding stock has depended on the radiographic diagnosis. There are numerous studies now looking for genetic indicators for CHD diagnosis. 8–11 Due to the canine genome’s sequencing and annotation, there is now renewed interest in studying the genetic causes of canine orthopedic disorders, especially those with a multifactorial etiology like CHD. The first commercial CHD genetic diagnostic test for Labrador Retrievers was recently released, but imaging diagnosis remains crucial for disease screening and treatment. Hip dysplasia also affects humans, and both conditions share phenotypic characteristics with regard to joint subluxation and the onset of osteoarthritis. 14 Humans, however, use a different primary medical strategy that focuses primarily on preventive care and produces positive outcomes. Because of the complexity of this disorder and the heterogeneity of human populations, molecular CHD studies are currently regarded as helpful for understanding the genetic basis of analogous conditions in humans, specifically hip osteoarthritis. 12 The main goal of this review is to present and discuss medical aspects of CHD for which there is insufficient knowledge, necessitating significant current research efforts.
In some breeds of working and pet dogs, CHD prevalence is over 50%, making it a persistently common trait. It is most prevalent in large and giant breeds. 2 There is no relationship between the disease’s clinical manifestation and the radiographic changes. 2,6 Due to hip instability in puppies under a year of age or chronic pain from osteoarthritis in adult dogs, the clinical signs of CHD are more noticeable in these groups of dogs. Chronic hip changes, such as fibrosis and thickening of the joint capsule, improve limb function and joint stability in middle-aged animals while masking the clinical signs and functional limitations. 6,17 Clinical signs warrant medical and/or surgical treatment. Due to the lack of pathognomonic clinical signs for CHD, early intervention is difficult in puppies at risk of developing CHD (18,19). Preventive conservative or surgical management may be indicated. Common clinical symptoms include: mild to moderate lameness; abnormalities in gait and running, such as bunny hopping and shortened strides; difficulty rising; and reluctance to climb stairs. 21.
Imaging procedures used for diagnosis or treatment can provide details about the hip joint’s conformation. 21,22 These medical tests are typically carried out on sedated or anesthetized animals and fall into two categories: assessing hip joint laxity (HJL), which is primarily used on young animals; and identifying clinical or radiographic signs of osteoarthritis, such as crepitation and a reduction in range of motion on joint palpation or degenerative joint disease (DJD) signs on radiographs. 1,21 However, the development of medical CHD screening methods for young, conscious animals, akin to the examination of hip dysplasia in newborn human infants, would be very beneficial. 1 For the past 50 years, the primary focus of CHD research has been the imaging diagnosis of the condition for reproductive control. Clearly, the primary focus in human medicine has been different, attempting to improve diagnostic precision and preventive management. 1,15.
The Ortolani test is the most widely used physical examination technique in veterinary medicine to identify HJL in young (4–12 month old) dogs. 23,24 Other clinical tests, such as the Barlow’s and Barden tests for puppies under 4 months of age, are also described, but their clinical validity is less certain. 1,17 The patient is placed in a lateral or dorsal recumbent position while the dog is awake, sedated, or anesthetized to perform the Ortolani test. With the hip at a normal weight-bearing angle, perform the first step of the test, which consists of applying proximal force to the stifle joint on the non-dependent limb, and then slowly abduct the joint while maintaining this force. The dysplastic femoral head may be displaced dorsally beyond the dorsal acetabular rim in hips with abnormal laxity (in the first step), and then limb abduction promotes its reduction back into the acetabulum (in the second step), which results in a typical palpable and/or audible clunk of variable magnitude that is known as a positive Ortolani sign (Figure 1). Even though HJL may be present, advanced CHD with destruction of the acetabular rim or in puppies younger than 4 months of age with an insufficient acetabular ossification can lead to false negative cases based on the Ortolani maneuver. 17,24,25 When applied to dogs under the age of one year who later developed moderate or severe CHD, the Ortolani test demonstrated excellent sensitivity in prediction of CHD. 24.
Since its initial description in 1935, radiography has been the standard technique for making a conclusive diagnosis of CHD. To diagnose and treat canines with clinical CHD or for genetic screening purposes, this imaging technique employs various radiographic views of the hip joint. It is recommended that all of these radiographic procedures be carried out while the patient is sedated or under anesthesia in order to ensure precise positioning and passive HJL induction. Given the complexity of the subject and the goals of this review, we will focus on radiographic studies used for CHD genetic screening that look for signs of DJD or HJL, the primary risk factor for CHD.
Utilizing radiographic techniques like PennHIP,26 dorsolateral subluxation (DLS),27 Flückiger,28 and half-axial position methods, radiographic information on HJL is obtained. Using the standard ventrodorsal hip-extended view (SVDV), 22 DJD symptoms are assessed. 2,29,30.
The PennHIP is the most widely used and was the first of this group of techniques. It was created in the 1980s at the University of Pennsylvania with the primary goal of controlling CHD breeding. 26 This method’s precocity—it can be accurately performed on dogs as young as 16 weeks, as opposed to 1 or 2 years for earlier screening methods—is one of its main advantages. The three hip radiographic views used in the PennHIP method—hip-extended, compression, and distraction—require certified participants. 26 The distraction view is used to measure HJL. It involves placing the dog in dorsal recumbency, keeping the hips in a neutral position, and using the PennHIP distractor between the hind limbs as a fulcrum to forcefully lateralize the femoral heads. 26 The radiographs are sent to the University of Pennsylvania’s PennHIP Analysis Center for a formal report, and the dogs are ranked alongside the other canines of their breed in the database. The distraction index (DI), which gauges the relative amount of femoral head displacement from the acetabulum, is used to evaluate the HJL in the distraction view. 3,26 A tight hip is represented by a DI of 0 and a loose hip is represented by a DI of 1. 26.
The HJL is calculated as the DLS score, which is also a passive stress radiographic or tomographic imaging technique. 27 The hip stress is caused by weight bearing. The DLS score has a strong correlation with DI. This technique was used to assess the chondro-osseous acetabular and femoral head structure in dogs at 4 and 8 months of age as a measure of functional joint stability. 27,31.
Similar to how the DI is estimated, the Flückiger method estimates the HJL using the subluxation index. 28 The dorsocranial force applied by the examiner while the dog is in the dorsal recumbent position causes stress in the hip joints. 28 The research was conducted in adult animals along with the SVDV to better evaluate the quality of the hips, but no follow-up studies were published.
A trapezoidal-shaped distractor was used to position the dog in the half-axial position while carrying out the hip stress in a manner similar to the PennHIP. The juvenile pubic symphysiodesis (JPS) is used to measure the HJL using this method primarily for the purpose of early CHD diagnosis and treatment.
The SVDV, a standard radiographic view employed in dogs older than 1 (according to the Fédération Cynologique Internationale [FCI] system) or 2 years (according to the Orthopaedic Foundation for Animals [OFA] system), is used to assess the DJD. 1,29 This view has been used since the 1960s. 32 The dog is positioned on the X-ray table in a dorsal recumbent position with its hind limbs extended parallel to one another and its stifles internally rotated. Numerous international systems, such as the FCI,1 OFA,29 British Veterinary Association/Kennel Club (BVA/KC),30 and the Flückiger33 method, are used to assess DJD. The FCI,1 OFA,29, UK, Australia, and Switzerland, respectively, have more influence in continental European countries. These scoring systems may be equal because they all base their primary criteria on the degree of subluxation, joint congruence, and remodeling of the femoral head and acetabulum (Table 1). However, due to their arbitrary nature, these direct comparisons between grades and schemes are regarded as speculative. The FCI method requires a minimum age of 12 months in medium breeds, while the OFA method requires a minimum age of 24 months. Additionally, FCI scrutinizers are not certified, and FCI, OFA, and BVA/KC are voluntary screening programs. The SVDV is not strongly evaluative of HJL. It is underestimated. Internal rotation of the stifles and parallel hip extension twist the hip soft tissues, tightening the tensile components of the joint capsule and potentially reducing some degree of luxation. 26.
The standard method for determining a developmental hip dysplasia diagnosis in newborn humans is ultrasound. 35 However, it is not advised to use ultrasound in puppies to confirm CHD because the acetabulum cannot be assessed after 8 weeks of age because acetabular chondro-osseous alterations and femoral head ossification are only visible after this time. 17 Later HJL and CHD were associated with elevated synovial fluid volumes in hip joints found by magnetic resonance imaging in 8-week-old puppies. 17 To measure HJL in puppies between the ages of 8 and 16 weeks, dynamic ultrasonography was used. Using computed tomography, the 36 HJL and osseous acetabular structure can be evaluated with confidence. 27.
Young dogs with clinical CHD predisposition have some preventive conservative and surgical treatments suggested. 7,19 To prevent obesity and build muscle, the main conservative management recommendations center on limiting food intake and engaging in moderate weight-bearing activity. 1,37 Disease-modifying osteoarthritis medications administered intravenously are advised as they may slow cartilage matrix breakdown, encourage its synthesis, and lessen pain and inflammation. 20 Anti-inflammatory or analgesic drugs are useful for treating pain and lameness, but they should only be used temporarily due to their unfavorable side effects. However, since their capacity to stop the onset and progression of osteoarthritis is at best limited, the long-term efficacy of this conservative treatment is in doubt. 7,19.
JPS is a surgical procedure used on puppies between the ages of 14 and 20 weeks who are at risk of developing CHD19,38, with better results seen when surgery is carried out at 15 weeks. 38 JPS is a minimally invasive procedure that works by heating chondrocytes in the pubic growth plate to necrosis. 19,38 Premature closure of the pubic growth plate causes an underdeveloped ventral pelvis and normal dorsal development. 7 As a result of this altered pelvic growth, the acetabular coverage of the femoral head is increased and the subluxation forces are decreased. 38 This method has been suggested for puppies with mild to moderate CHD symptoms, but not for animals with severe CHD symptoms. In the JPS, acetabular ventroversion progresses slowly, and in severe cases of CHD, the femoral head slides laterally and remains unstable despite the dorsal acetabular edge becoming round. 19.
Animals between the ages of 5 and 12 months old, without radiographic evidence of DJD and with little to no clinical evidence of CHD, may benefit from triple pelvic osteotomy as a reasonable surgical treatment option for CHD. Triple pelvic osteotomy, however, works better in dogs under 7 months of age when it comes to halting the onset of DJD. 7 The pubis, ischium, and ilium of the pelvis are cut, rotated, and the ilium is fixed with a surgical plate. This surgical procedure causes the acetabulum to rotate ventrolaterally and immediately increases the stability of the femoral head. But dogs’ hips that already have osteoarthritic changes or have high HJLs continue to deteriorate and have a worse outcome. 7 Treatment should be administered when osteoarthritis is already advanced in order to reduce pain and preserve joint function. 18,39.
The pain brought on by abnormal bone-to-bone hip joint contact is lessened by femoral head and neck excision, but the full range of hip motion and limb function are not always maintained. The best course of action to maintain limb functionality over the long term is a total hip replacement.
Due to the small additive effect of numerous genes, CHD is a complex polygenic disease. 4,8 Environmental variables like sex, age, and body weight can affect how the disease manifests and how severe it is. With adequate femoral head and acetabular congruence at birth, hips appear to be normal and rule out congenital heart disease (CHD). The hip joint’s development is thought to be most crucial during the first 60 days of a puppy’s life. 16 During this time, modeling in accordance with the stress loading is possible for the proximal femoral head and neck conformation as well as the depth of the acetabular cavity. 15.
The normal weight-bearing force in a congruent hip joint travels across the articular cartilage between the femoral head and the acetabulum. The reduction in contact between the cartilaginous surfaces, the early destruction of chondrocytes by increasing pressure, and the cyclic cascade of osteoarthritis are all favored by joint incongruence. High pelvic muscle mass, low levels of the hormones that encourage soft tissue relaxation, a small synovial joint volume, and low intracapsular pressure all contribute to stability and prevent the onset of CHD symptoms. 26 The HJL is the main risk factor, which has been thoroughly evaluated in a radiographic study that is linked to the development of CHD. 40 The amount of transmitted hip forces is directly correlated with the conformation of the acetabular and proximal femoral head and neck. 41 As a result, hip conformation, cartilage susceptibility to pressure forces, joint soft tissues, or even hormonal factors can all be related to genetic factors associated with CHD.
Published heritabilities for CHD traits vary and frequently fall between 0 and 1. 1 to 0. 60. 12,42 Heritability estimates differ depending on the trait, calculation method, selection, population, and estimation sample used. 5,42 For example, heritability reached as high as 0. 83 for passive hip laxity in the Portuguese breed of Estrela Mountain dogs. 3 There will be more genetic advancement per generation when choosing traits with higher heritabilities and comparable selection pressures. 1.
Choosing breeding stock with low hip scores will help to reduce the prevalence of hip dysplasia.
Veterinarians in practice are at the forefront because there is no ideal medical or surgical treatment and their primary focus is on CHD prevention through reproductive control. 43 It is evident that veterinary medicine places a high priority on the selection of breeding stock. In some nations, control CHD programs based on the hip’s radiographic phenotype quality were implemented as early as the 1960s. 44–46 These programs were based on DJD signs and hip congruence scores as well as radiographic CHD screening using the SVDV. The breeder’s subjective pedigree evaluation and each dog’s hip phenotype were used to determine which breeding stock to use. The prevalence and severity of CHD as determined by phenotype-based genetic screening vary somewhat between nations and breeds. Only the better hip phenotypes are examined in studies using these databases when the CHD control schemes, such as the OFA, FCI, and BVA/KC, are voluntary. 2,42 For Labrador Retrievers, the total genetic improvement over four decades (1970–2007) corresponded to only 17% of the total phenotypic standard deviation using the OFA scoring system and the best linear unbiased prediction method for the estimation of breeding values and its application in the selection for hip joint conformation. But compared to radiographs of dogs with severely dysplastic hips, radiographs of dogs with normal-appearing hips are several times more likely to be submitted for evaluation in the OFA system. 47 For instance, over five generations of selection, the prevalence of CHD in a closed breeding colony of German Shepherd dogs and Labrador Retrievers fell from 55% to 24% and from 30% to 10%, respectively. 46 In Sweden, the prevalence and severity of CHD were less reduced by selective breeding. 44 The general CHD control program was even thought to be ineffective in lowering the prevalence of CHD in different dog breeds in some other nations, such as Finland. There are no reports of the PennHIP method’s effectiveness in lowering the prevalence of CHD in various dog populations. Since studies have shown that HJL has a higher heritability than the CHD scores based on DJD, theoretically, it is a promising method. Because of its sensitivity to environmental factors, CHD control programs that solely rely on individual phenotype have not had the desired level of success. CHD genes can still be present in animals with normal individual radiographic phenotypes; these genes will be passed down to their progeny and kept in the population. When selecting farm animals for complex polygenic traits (phenotype expression is influenced by environmental factors), such as milk yield or growth rate, estimated breeding values (EBV) are frequently used. Therefore, these traits’ phenotypic manifestations are very similar to CHD and are influenced by both heredity and environment (28,49). Since the EBV for CHD is a genetic parameter derived from the hip quality of relatives, it is more indicative of the dog’s genetic quality12,44 and enables the tracking of genetic trends in dog populations50, making it a recommended parameter for CHD selection. 51,52.
Genetic markers in linkage disequilibrium have been linked to CHD genes thanks to the rapid advancement of high-throughput sequencing technology and the appearance of high-density genome-wide single nucleotide polymorphism (SNP) canine arrays. 14,42 The molecular genetic data can be used for CHD selection, especially if the most illuminating SNPs are used to calculate an individual’s genomic breeding value (GBV). This type of genomic selection has been used successfully in livestock animal breeding programs and can be used to select against the occurrence of undesirable traits with greater genetic improvement. 10,42,43,53 In the near future, GBV might be favored as a way to enhance hip quality in CHD prevention plans. Pedigree and phenotypic information about a specific dog breed can be used to determine the EBV, and genomic information can be combined with that information to create a GBV prediction formula. The genotyping of a puppy for a group of instructive SNPs can then be combined with radiographic data and used to assess the puppy’s susceptibility to CHD and make decisions about the management of the breed.
The scientific community has validated and accepted the genetic etiology of CHD. 54 Todhunter et al. at Cornell University created the first molecular studies for CHD diagnosis in the 1990s. They started by looking for molecular genetic markers that were connected to quantitative trait loci (QTL) responsible for various CHD phenotypes. 9,55 A cross between the breeds of Labrador Retrievers and Greyhounds, which have high and low susceptibility to developing CHD, respectively, was carried out to maximize the linkage of genes to CHD traits. Twelve chromosomes were found to contain potential QTLs for various CHD traits. Additionally, 9 QTL were linked to the Norberg angle8 and the development of acetabular osteophytes. 56 Recently, more QTL were associated with other CHD traits. 10,57.
In several studies, a major QTL associated with CHD (contributing about 20% of variance) was suggested by pedigree and CHD phenotype analysis. 46,58–60.
However, the identification of genes is still difficult because the QTL region may contain hundreds of genes. Some researchers use SNPs and across-breed mapping to refine the QTL interval, shortening the linkage disequilibrium interval in the process. 4 Unrelated CHD-affected animals are likely to share more common disease alleles than the dog population as a whole. 4 Physical proximity to the responsible gene may exist between the associated SNPs. In order to identify common genetic variants for complex diseases, GWAS take into account the combined effect of multiple SNPs, which is significantly more effective than individual SNP analysis. Four SNPs were significantly associated with CHD on CFA3, 11, and 30, and two with osteoarthritis on CFA17 and 37 in eight different dog breeds using GWAS. 13 SNPs on chromosomes CFA14 and 37,61 CFA19, 24, 26, and 34,11 and CFA3, 9, 26, 33, and 34 were also linked to CHD in German Shepherd dogs. 62 In additional recent studies on Labrador Retrievers, four SNPs on chromosome CFA1 and 21, 10, and 31 SNPs on CFA1, 5, 8, 15, 20, 25, and 32 located within or close to 24 different genes were associated with CHD (Table 2). On CFA1, 8, 20, and 25, there are significantly associated regions with 63 candidate genes for the hypertrophic differentiation of chondrocytes and extracellular matrix integrity of basement membrane and cartilage. These findings encourage caution about the development of a marker-assisted, precise CHD diagnostic test in the near future because they support the complex genetic architecture of CHD, which is based on numerous genes with small individual effects. The use of CHD molecular diagnosis in genomic selection (many markers evaluated for their combined contribution) will likely be of immediate importance.
CHD was significantly linked to one mutation in the FBN2 gene on the CFA11 chromosome in Labrador Retrievers and other dog breeds. However, since the FBN2 locus only accounts for a small portion of the genetic trait variation in CHD, other genes must be involved in the condition. Studies on QTL and/or SNPs linked to other CHD phenotypes, like passive hip laxity, could shed more light on the genetics of this condition. 64 The greatest risk factor for CHD and the trait with the highest heritability is passive hip laxity. 3,40.
There is currently little known about the loci-linked hip dysplasia in humans because genetic studies on the developmental hip dysplasia in humans have not made much progress. Despite recent advances in whole-genome analysis in humans and the identification of several genetic variants linked to this condition in affected patients,65,66 understanding the genetics of hip dysplasia in humans can benefit from studies of the same kind in dogs.
An ideal tool for early detection of canines susceptible or resistant to CHD is a DNA-based test. In 2012, such a test was registered by Bioiberia. It was the first commercial marker-based DNA test for CHD susceptibility in the Labrador Retriever breed, and it went by the name of Dysgen. This test uses a DNA kit with seven SNPs to analyze blood samples. The dog is categorized into one of four risk groups for coronary heart disease (CHD) based on the Dysgen diagnosis: minimal, low, moderate, and high. However, the Dysgen diagnosis test’s effectiveness was not independently evaluated, and there are no published studies indicating that it was successful in preventing CHD at the population level. The producer advises breeding dogs with little to no risk of developing CHD. This is a first step in the molecular diagnosis of CHD, but CHD control programs still need to combine accurate phenotype screening, EBV, and knowledge of the available genetic tests until all the genes involved in the disease are discovered. Combining data on major gene genotypes and EBV will increase the effectiveness of selection, especially if the trait’s heritability is low. We also need a thorough understanding of the genetics underlying the prevalence of this condition at the population level because CHD affects a sizable number of different dog breeds, from the Portuguese Water Dog to the Alaskan Malamute, and they are all raised in various environments.
CHD remains one of the most prevalent orthopedic hereditary diseases in dogs despite phenotypic screening and breeding programs. Reproductive control programs have been a top priority in veterinary medicine for the past 50 years as a way to combat the disease because there is no ideal diagnosis or treatment for CHD.
Due to the numerous associated genes’ small individual effects, the genetic architecture of CHD is complex. Despite extensive global research, this fact makes the development of a marker-assisted accurate CHD diagnosis test challenging.
A better understanding of the genetic basis of conditions similar to CHD in humans may result from the molecular diagnosis of CHD, which will be based on genomic selection until all contributing and critical mutations are identified.
C Ginja received funding from the Fundaço para a Ciência e a Tecnologia, Portugal, through a Marie Curie/Welcome II fellowship (Ref DFRH/WIIA/15/2011), as well as from the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement number PCOFUND-GA-2009-246542. The authors acknowledge the expert review of the manuscript and valuable comments provided by R Todhunter (College of Veterinary Medicine, Cornell University).
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Utilizing radiographic techniques like PennHIP,26 dorsolateral subluxation (DLS),27 Flückiger,28 and half-axial position methods, radiographic information on HJL is obtained. Using the standard ventrodorsal hip-extended view (SVDV), 22 DJD symptoms are assessed. 2,29,30.
Veterinarians in practice are at the forefront because there is no ideal medical or surgical treatment and their primary focus is on CHD prevention through reproductive control. 43 It is evident that veterinary medicine places a high priority on the selection of breeding stock. In some nations, control CHD programs based on the hip’s radiographic phenotype quality were implemented as early as the 1960s. 44–46 These programs were based on DJD signs and hip congruence scores as well as radiographic CHD screening using the SVDV. The breeder’s subjective pedigree evaluation and each dog’s hip phenotype were used to determine which breeding stock to use. The prevalence and severity of CHD as determined by phenotype-based genetic screening vary somewhat between nations and breeds. Only the better hip phenotypes are examined in studies using these databases when the CHD control schemes, such as the OFA, FCI, and BVA/KC, are voluntary. 2,42 For Labrador Retrievers, the total genetic improvement over four decades (1970–2007) corresponded to only 17% of the total phenotypic standard deviation using the OFA scoring system and the best linear unbiased prediction method for the estimation of breeding values and its application in the selection for hip joint conformation. But compared to radiographs of dogs with severely dysplastic hips, radiographs of dogs with normal-appearing hips are several times more likely to be submitted for evaluation in the OFA system. 47 For instance, over five generations of selection, the prevalence of CHD in a closed breeding colony of German Shepherd dogs and Labrador Retrievers fell from 55% to 24% and from 30% to 10%, respectively. 46 In Sweden, the prevalence and severity of CHD were less reduced by selective breeding. 44 The general CHD control program was even thought to be ineffective in lowering the prevalence of CHD in different dog breeds in some other nations, such as Finland. There are no reports of the PennHIP method’s effectiveness in lowering the prevalence of CHD in various dog populations. Since studies have shown that HJL has a higher heritability than the CHD scores based on DJD, theoretically, it is a promising method. Because of its sensitivity to environmental factors, CHD control programs that solely rely on individual phenotype have not had the desired level of success. CHD genes can still be present in animals with normal individual radiographic phenotypes; these genes will be passed down to their progeny and kept in the population. When selecting farm animals for complex polygenic traits (phenotype expression is influenced by environmental factors), such as milk yield or growth rate, estimated breeding values (EBV) are frequently used. Therefore, these traits’ phenotypic manifestations are very similar to CHD and are influenced by both heredity and environment (28,49). Since the EBV for CHD is a genetic parameter derived from the hip quality of relatives, it is more indicative of the dog’s genetic quality12,44 and enables the tracking of genetic trends in dog populations50, making it a recommended parameter for CHD selection. 51,52.
The SVDV, a standard radiographic view employed in dogs older than 1 (according to the Fédération Cynologique Internationale [FCI] system) or 2 years (according to the Orthopaedic Foundation for Animals [OFA] system), is used to assess the DJD. 1,29 This view has been used since the 1960s. 32 The dog is positioned on the X-ray table in a dorsal recumbent position with its hind limbs extended parallel to one another and its stifles internally rotated. Numerous international systems, such as the FCI,1 OFA,29 British Veterinary Association/Kennel Club (BVA/KC),30 and the Flückiger33 method, are used to assess DJD. The FCI,1 OFA,29, UK, Australia, and Switzerland, respectively, have more influence in continental European countries. These scoring systems may be equal because they all base their primary criteria on the degree of subluxation, joint congruence, and remodeling of the femoral head and acetabulum (Table 1). However, due to their arbitrary nature, these direct comparisons between grades and schemes are regarded as speculative. The FCI method requires a minimum age of 12 months in medium breeds, while the OFA method requires a minimum age of 24 months. Additionally, FCI scrutinizers are not certified, and FCI, OFA, and BVA/KC are voluntary screening programs. The SVDV is not strongly evaluative of HJL. It is underestimated. Internal rotation of the stifles and parallel hip extension twist the hip soft tissues, tightening the tensile components of the joint capsule and potentially reducing some degree of luxation. 26.
An ideal tool for early detection of canines susceptible or resistant to CHD is a DNA-based test. In 2012, such a test was registered by Bioiberia. It was the first commercial marker-based DNA test for CHD susceptibility in the Labrador Retriever breed, and it went by the name of Dysgen. This test uses a DNA kit with seven SNPs to analyze blood samples. The dog is categorized into one of four risk groups for coronary heart disease (CHD) based on the Dysgen diagnosis: minimal, low, moderate, and high. However, the Dysgen diagnosis test’s effectiveness was not independently evaluated, and there are no published studies indicating that it was successful in preventing CHD at the population level. The producer advises breeding dogs with little to no risk of developing CHD. This is a first step in the molecular diagnosis of CHD, but CHD control programs still need to combine accurate phenotype screening, EBV, and knowledge of the available genetic tests until all the genes involved in the disease are discovered. Combining data on major gene genotypes and EBV will increase the effectiveness of selection, especially if the trait’s heritability is low. We also need a thorough understanding of the genetics underlying the prevalence of this condition at the population level because CHD affects a sizable number of different dog breeds, from the Portuguese Water Dog to the Alaskan Malamute, and they are all raised in various environments.
There is currently little known about the loci-linked hip dysplasia in humans because genetic studies on the developmental hip dysplasia in humans have not made much progress. Despite recent advances in whole-genome analysis in humans and the identification of several genetic variants linked to this condition in affected patients,65,66 understanding the genetics of hip dysplasia in humans can benefit from studies of the same kind in dogs.
Complex diseases like CHD have a fundamentally different genetic makeup than monogenic disorders. The former result from the interaction of a large and unknown number of environmental and genetic factors, the majority of which have small effects, whereas the latter are, by definition, caused by a small number of genetic changes with high penetrance [6]. Though it can be expected that the vast majority of genetic loci contributing significantly to a complex disease, in both humans and non-human mammals cared for by humans, will be identified in the not-too-distant future, given the rapid technological development in genetics research [6]. Even though identifying statistical genotype-phenotype relationships is only the first step towards understanding the causes of disease, such associations can still be immediately useful because they may serve as the foundation for diagnostic or prognostic tests. This also covers the prognosis of canine illnesses like CHD and CED.
935 dogs in total had their status for CHD evaluated () Diagnostic data for CED was also available for 928 of these. Most animals were affected by neither disease (phenotype class 1). More specifically, 657 dogs (70. 3%) were free of CHD whilst 714 (76. 9%) lacked signs of CED. Of the 287 animals suffering from CHD, 179 (62. 4%) showed a mild phenotype (class 2) whereas 25 (8. 7%) were diagnosed with severe CHD (class 5). Most people (class 3: 53, 18) had a mild to moderate phenotype. 5%; class 4: 21, 7. 3%). For CED, 70 of the 214 affected dogs (32 7%) had a mild form (class 2), compared to 37 (17%). 3%) had severe CED (class 5). Some 39 (18. 2%) and 68 (31. Animals with mild to moderate CED (class 3 or 4, respectively) were diagnosed in 8% of the cases. In the 525 dogs (56), the two conditions were discovered to be significantly related. 6%) had neither condition whilst 82 (8. 8%) had both (OR: 1. 73, 95% CI: 1. 25–2. 38).
The so-called “receiver-operating characteristic curve” (ROC) can be used to evaluate the usefulness of a predictive test with a continuous outcome, such as, for example, GBV or GBV(S). The ROC compares the likelihood of true positive results to the likelihood of false positive results that would result from categorizing the test result using different thresholds. The AUC sensibly ranges from 0. 5 (equivalent to tossing a coin, i. e. total lack of predictive capability) to 1. It does not depend on the likelihood that the disease in question is present (0 is a perfect prediction). According to Janssens et al. [9], an AUC of around 0. For screening purposes, 8 is typically regarded as both necessary and sufficient. However, Distl et al.’s proposed genomic breeding value GBV [2] achieved an AUC of only 0. 523 for CHD in our study. We subjected the SNP genotypes to post hoc logistic regression analysis, allowing for all potential additive and dominance effects, because this rather poor performance, in theory, could have reflected inadequacy of the marker weights used for the definition of GBV. However, even the complete regression model with all 17 markers produced an AUC of just 0. 610 in our study. Additionally, it was discovered that this outcome was largely dependent on just two markers, TiHo25 and TiHo26. All other markers lacked even minuscule predictive value for CHD. Notably, applying the 17 SNPs to CED revealed that they also had no discernible predictive value, which was expected given that CED served as a sort of negative control in the current study.
A notably negative trend for CHD (but not for CED ()) emerged upon closer examination of the association between the phenotypic classification and GBV. The median GBV fell from 1 with increasing CHD classification (from class 1 to class 5). 442 via 1. 134 (classes 2, 3 and 4 combined) to -1. 234 (class 5). GBV as described in Patent Specification EP 2 123 777 B1 instead offers a minor utility predictive “test” (post hoc AUC: 0). 622) for severe CHD, but only after flipping the way the test result is interpreted.
According to the specification of patent EP 2 123 777 B1 (S2 Table), PCR primers for the amplification of 17 CHD-associated markers were created. But only information about the allelic and flanking DNA sequences was used if it could be tested experimentally in our own lab. In fact, it turned out that the information provided in the patent specification was incorrect, necessitating a revision of the DNA sequence at four of the markers (TiHo1, TiHo18, TiHo19, and TiHo35).
VANCOUVER, Wash. –(BUSINESS WIRE)–Wisdom Health Genetics, the pioneer in pet genetics and creator of the WISDOM PANELTM dog DNA test, announced today that a study it collaborated on with the University of Helsinki was published in BMC Genomics.
Research reveals the intricate genetic makeup of canine hip dysplasia and validates more than 20 previously discovered genetic risk variants.
Our coalition includes the award-winning WhistleTM GPS dog tracker and health monitor, the cutting-edge Pet Insight Project, our ground-breaking science stream that uses AI to turn billions of data points into actionable insights, and partnerships like our Leap Venture Studio accelerator that supports innovators and start-ups to bring new solutions to pet parents. Wisdom PanelTM is the industry leader in genetic health screening and DNA testing for dogs. Kinship is a division of Mars Petcare. Learn more at www. kinship. co.
About Kinship Partners, Inc. Kinship is here to support all pet parents in a professional manner. We owe our pets the best treatment because they improve us as people. We use our data, products, and services to help people be the best pet parents they can be as allies to pet parents learning on the job. We bring together innovators in the pet care industry to dismantle barriers, unlock opportunities, share knowledge, and advance our collective understanding. We’re assisting the world in finding better ways to care by reimagining the pet parenting experience and boosting people’s confidence.
Genetic samples from a cohort of more than 1600 dogs from ten different breeds were examined by researchers from the University of Helsinki and Wisdom Health Genetics. Across 14 chromosomes, the study validated more than 20 previously identified genetic regions linked to canine hip dysplasia; while 20 of the loci were linked to particular breeds, one locus was linked to all ten breeds in the study.
FAQ
Are there genetic markers for hip dysplasia in dogs?
The entire health testing protocol consists of phenotype (physical examinations) for some diseases and genotype (DNA tests) for others. For hip dysplasia, one of the most frequent physical examinations is performed. It is a complex polygenic disease with no genetic test.
Can you genetically test for hip dysplasia?
In conclusion, finding a genetic test to identify all patients at risk for hip dysplasia is unlikely, just as finding a genetic test to identify everyone at risk for cancer, heart attacks, or stomach ulcers is unlikely.
Is there a DNA test for hip dysplasia in dogs?
Hip dysplasia is diagnosed and quantified by radiographic examination of the hip joint, and many breeds use the diagnosis to guide breeding decisions. In a study using Spanish Labrador Retrievers, a prognostic genetic test (the Dysgen test) based on seven associated SNPs was created.
Is there a blood test for hip dysplasia in dogs?
Currently, a blood test or genetic test cannot be performed by veterinarians to identify canine hip dysplasia. However, hip radiographs or x-rays can be used to assess specific animals. Hip radiographs are evaluated by Orthopedic Foundation of America® (OFA) and PennHip®, two widely recognized organizations.