Canine hip dysplasia is a common inherited developmental orthopedic disease of medium- and largebreed dogs that is characterized by various degrees of laxity and incongruity in the hip joint. Canine hip dysplasia is a polygenic or complex trait, the underlying molecular genetic basis of which is unknown. On the basis of population genetic analyses, it is suspected that a few major QTLs, with minor contributions from others, likely contribute to the CHD phenotype.1 Twelve putative QTLs have been discovered that may contribute to the dysplastic phenotype within a Labrador Retriever–Greyhound crossbreed pedigree.2 On the basis of genome-wide significance thresholds, QTLs on each end of canine chromosome CFA01 were identified that contributed separately to the left and right Norberg angle in a kindred of Portuguese Water Dogs.3 One challenge at present is to discover the genes and their mutations that exist within these QTLs and contribute to CHD.
Hip joint osteoarthritis has generally been considered to be an inevitable sequela to CHD and, in the absence of severe traumatic injury to the hip joint, has been considered to be diagnostic for antecedent CHD. In a dysplastic hip, poor hip joint congruity and subluxation lead to abnormal focal loading and stress on articulating surfaces.4 This leads to perifoveal articular cartilage erosion, capsular and round ligament thickening, and synovial effusion and synovitis. These early changes are undetectable radiographically but can be clinically important and lead to signs of joint pain and physical disability. Dysplastic dogs often develop lameness and gait abnormalities from 3 to 8 months of age. Subchondral sclerosis and osteophyte formation develop later in the progression of disease.5,6 Development of these more advanced lesions is necessary for radiographic diagnosis of osteoarthritis secondary to antecedent CHD. Unfortunately, the radiographic alterations consistent with hip joint osteoarthritis develop late in disease progression and are therefore less than ideal for use in guiding selective breeding programs. Also, a dog's phenotype does not always reflect the underlying genotype; a nondysplastic dog may carry 1 or more alleles that promote CHD or secondary osteoarthritis and could therefore produce dysplastic offspring. Nongenetic or environmental influences may contribute some variation in the expression of secondary osteoarthritis, which can be exacerbated by obesity and rapid growth.5–9
Some breeds of dogs may tolerate passive hip joint laxity better than other breeds.10,11 Dogs of certain breeds develop radiographically apparent hip joint osteoarthritis in association with CHD more quickly than dogs of other breeds.10 Molecular genetic evidence for this breed effect on development of secondary hip joint osteoarthritis is beginning to emerge. A QTL for acetabular osteophyte formation secondary to CHD in Portuguese Water Dogs was detected on the CFA03 chromosome.12 Abnormal mechanical loading associated with the severity of hip joint subluxation during ambulation is likely responsible for some of the variation observed in severity of secondary hip joint osteoarthritis. However, this finding in Portuguese Water Dogs suggests that there may be QTLs that regulate the severity of secondary hip joint osteoarthritis that are separate from or interact with those that regulate expression of CHD. Identifying the molecular genetic basis of both CHD and secondary osteoarthritis will provide a foundation for understanding the link between the 2 conditions.
Several authors have discussed the relationship between hip dysplasia and early-onset hip joint osteoarthritis in humans.13–17 The 2000 NIH conference report on osteoarthritis stated that in humans, osteoarthritis appears to be strongly genetically determined; genetic factors account for at least 50% of the variance in cases of osteoarthritis of the hands and hip joint.18,19 Susceptibility loci for human hip joint osteoarthritis have been mapped to several chromosomes with various levels of statistical support.20,21 Recent evidence suggests that polymorphisms in signal transduction genes or transcriptional regulatory sequences are a major route through which osteoarthritis susceptibility is expressed locally in the joint.21
Quantitative (ie, complex) traits such as CHD and hip joint osteoarthritis are regulated by alleles at loci that act additively, and some alleles may also have dominance. In a Labrador Retriever–Greyhound pedigree, the inheritance pattern of the distraction index was determined to be additive, and the inheritance pattern of the dorsolateral subluxation score was both additive and dominant.22 Knowledge of the inheritance pattern will enable the optimum statistical approach to be used for mapping the QTL regulating hip joint osteoarthritis in dogs and for identifying the genes within the QTL. The aim of the study reported here was to establish the inheritance pattern of hip joint osteoarthritis in Labrador Retrievers, Greyhounds, and their crossbred offspring in an experimental pedigree.
Quantitative trait locus
Canine hip dysplasia
SAS System for mixed models, SAS Institute Inc, Cary, NC.
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