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An update on hip dysplasia in dogs

4/21/2019

 
By Carol Beuchat PhD

Hip dysplasia remains one of the most significant causes of pain and disability in dogs despite decades of research into the causes and diligent efforts by breeders to reduce risk through selective breeding. A new review article aimed at veterinarians provides a useful summary of the current state of our understanding of its causes (Witte 2019). The comments here are detailed in that review.
Hip dysplasia is a so-called "developmental disease", because the first signs of abnormality appear in young puppies.

​A key sign of early risk is "coxofemoral laxity", a loose fit of the head of the femur in the hip socket. This looseness means the head of the femur is not held snugly in the socket but can move around, putting abnormal pressures on the sides and rim of the socket. This poor fit results in deformation of the socket and ultimately leads to osteoarthritis and the condition of hip dysplasia.
​
Genetics clearly plays a role in the development of hip dysplasia. However, the condition is complex and clearly polygenic and specific genes that are predictive of hip dysplasia across breeds have not been found.

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Top: Femoral head well-seated in the hip socket with good coverage by the acetabular rim. The loading forces will be evenly distributed over a large surface area. Bottom: Femoral head is subluxated (pulled away) from the hip socket as in a hip with laxity. The loading forces will not be evenly distributed but focused on the weaker rim of the socket. (Witte 2019)
Heritability is the fraction of the variation in hip phenotype that is accounted for by variation in genotype. The higher the heritability of a trait, the more it will respond to selection. Heritability of hip dysplasia varies widely depending on the breed, the sample population, and the criterion used to assess phenotype. Values for heritability are usually about 0.2-0.3 using the OFA (Orthopedic Foundation for Animals) hip scoring method, while much higher heritability (0.8) has been reported in some dogs evaluated using PennHIP (Pennsylvania Hip Improvement Program). 
​
A number of non-genetic (environmental) factors are known to affect the risk of developing hip dysplasia, and some of these appear to be especially critical to manage properly in the puppy. Housing on a slippery floor, access to stairs, and some types of exercise can significantly increase risk in puppies. Higher weight at birth and while growing elevates risk. On the other hand, dogs raised on farms and those born in spring and summer are less likely to develop hip dysplasia. Aside from nutritional deficiencies, or overconsumption that leads to overweight, there is no evidence that the type of the diet plays a role in development of dysplasia. Although exercise in the adult might lead to clinical signs of pain or lameness, there is little evidence that the amount of exercise alters the progression of development of osteoarthritis once the dog matures. Dogs neutered before 6 months have a higher risk of developing hip dysplasia.

Managing the risk of hip dysplasia remains a challenge for breeders and dog owners. Breeders must consider both genetics in mate selection and environmental factors, especially when the puppies are young. When puppies go to their new homes, owners must be educated about the factors that elevate the risk of developing hip dysplasia, especially weight, stairs, and unsuitable exercise and activities.
​
​
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(Witte 2019)

You can learn more about hip and elbow dysplasia in ICB's online course "Understanding Hip & Elbow Dysplasia", which covers the most up-to-date information about causes, treatment, and prevention.

Learn more HERE.​​​​

REFERENCES
Witte PG, 2019. Hip dysplasia - understanding the disease. Companion Animal 24:77-81.

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Addison's disease and those doggone DLAs

4/20/2019

 
By Carol Beuchat PhD

The adrenal cortex is the outer layer of the adrenal gland, which is a small organ near the kidneys. It secretes hormones that are part of the stress response (e.g., cortisol), and it also produces aldosterone, a hormone essential for maintaining normal levels of minerals involved in the regulation of blood pressure.

In some dogs (and in humans), the immune system fails to recognize the tissue of the adrenal cortex as "self" and destroys it. The result is Addison's disease, which can be fatal. Addision's is especially common in some breeds, including Standard Poodles, Portuguese Water Dogs, Cocker Spaniels, Nova Scotia Duck Tolling Retrievers, and Bearded Collies. The frequency in Poodles is relatively high, estimated at 5-10% (Famula et al. 2003).

Studies looking for a genetic basis for Addison's have identified SNPs that might be associated with the disease, but causative genes have not been found. Because Addison's is an auto-immune disease, we might expect to find relationships between risk and the genes of the immune system. In dogs, these genes are called the dog leukocyte antigens (DLA), and they come in combinations called haplotypes. There has been some success in identifying DLA haplotypes that confer risk of disease in several breeds (Hughes et al. 2010, Massey et al. 2013, Pedersen et al. 2015). 

A study just out takes a closer look at the association between DLA haplotypes and Addison's Disease in Poodles, using a larger sample size than previous studies and also looking for potential associations related to sex of the dog (Treeful et al. 2019). The results are both interesting and sobering. While the data are for Poodles, the implications are relevant for every breed, so you should read this even if you don't have Poodles.

Treeful and colleagues studied 265 Standard Poodles that included 110 affected dogs and 101 that were unaffected. They identified 16 DLA class II haplotypes in this population of dogs.

Haplotype 1 was by far the most common and comprised 72% of all haplotypes (black & white figure). Eight haplotypes were represented only once or twice and collectively accounted for 2% of the total (designated as "other" in the graph). The remaining seven haplotypes (haplotypes 2-8) comprised 1 to 7% of the total.

There was no difference between males and females in the distributions of haplotypes 1-8 (colored figure). But in males, haplotype 1 conferred an elevated risk of Addison's Disease, and risk was even greater when the alleles were homozygous. In females, haplotype 5 was associated with increased risk of Addison's Disease.

These data reveal that the effect of the implicated DLA haplotypes on disease risk is related to the sex of the dog. This means that selective breeding to reduce the incidence of Addison's Disease in the Poodle population will be complicated by the fact that the haplotypes that confer elevated risk are different in males and females.

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​Furthermore, haplotypes 2-8 and "other" are uncommon in the breed, which means that the options for "breeding away" from haplotype 1 to reduce the incidence of Addison's in male dogs will be limited by the paucity of dogs to breed to.  Haplotype 5 is a risk for females, presenting similar problems.

The problem here is that we know very little about the DLA genes and how they work. In mammals, the immune system genes have the highest diversity because the individuals with the most diversity also have the highest rates of survival. This tells us that high diversity is important, and we can surmise that low diversity will compromise the function of the immune system. In dogs, limited diversity from a small number of founder dogs, together with inbreeding and loss of diversity through selection and genetic drift, has resulted in both reduced diversity and uneven representation of haplotypes as seen in the Poodle, where haplotype 1 is overrepresented.

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The way we breed dogs defeats the method of natural selection that ensures that high diversity in the DLA is retained because it improves survival. Inbreeding to reduce variation in the traits important to breed type will also reduce variation in the DLA haplotypes. This compromises the function of the dog's most fundamental defense system against pathogens, parasites, and disease. The immune system also plays a critical role in prevention of cancer, by identifying and destroying cells that might grow uncontrollably. ​

We already knew that there was reduced diversity in the DLA genes in Poodles (Pedersen et al. 2015), as there probably is in most breeds. But the data in this paper make it clear that restoring diversity and normal function is not going to be a simple matter of breeding away from risk alleles. There are many immune system disorders in dogs, and others in Poodles, and we know very little about their genetic basis. Breeding strategies to alter the frequencies of DLA haplotypes in the population could result in an increased frequency of some other immune system dysfunction.

Breeders are likely to be strongly tempted to use information about DLA haplotypes to inform breeding decisions, based on the perception that the frequencies of some allele should be increased and others decreased. Dr Lorna Kennedy, who has studied the canine DLA genes for many years, cautions against this. (Note that Kennedy uses the term MHC, which stands for "major histocompatibility complex,"  the broad class of immune system genes to which DLA belong.)
"Auto-immune diseases are complex diseases. These are diseases that occur as a result of the influence and interaction of multiple genes. However, the critical feature of these diseases is that they only occur after exposure to an environmental trigger.

So whether or not someone (or some dog) will develop the disease, depends on the particular combination of variants of the risk genes that they have, plus exposure to the environmental trigger.

Many canine auto-immune diseases have been shown to have MHC associations. Can we use DLA information to reduce disease susceptibility? There has been a suggestion that if a DLA allele or haplotype has been associated with a specific disease in a breed, then we should use this MHC information in mate selection to reduce the frequency of that haplotype.

I believe very strongly that we should not do this.

There may be a reason why a haplotype is at low frequency in a breed. Perhaps it is associated with another disease that is currently rare in the breed. Auto-immune diseases are complex, and will have multiple risk and protective gene associations.

​
Manipulating MHC haplotype frequencies may not reduce disease risk, and could cause more problems." (Kennedy 2011)

The one recommendation Kennedy makes is to avoid producing puppies that will be homozygous for DLA haplotypes. Otherwise, as she notes, because the interactions among genes are complex and the workings of the immune system poorly understood, breeders should not attempt to alter haplotype frequencies through selective breeding. At the very least, if there is a serious problem in a breed, breeders could consult with experts that can advise on the best course of action.
​
Perhaps the best strategy, once again, is to protect the existing genetic diversity in your breed and avoid producing homozygosity by inbreeding. 

REFERENCES

Famula TR, JM Belanger, & AM Oberbauer. 2003. Heritability and complex segregation analysis of hypoadrenocorticism in the Standard Poodle. J Small Animal Practice 44: 8-12. doi.org/10.1111/j.1748-5827.2003.tb00096.x

Hughes AM, Jokinen P, Bannasch DL, Lohi H, Oberbauer AM (2010) Association of a dog leukocyte antigen class II haplotype with hypoadrenocorticism in Nova Scotia Duck Tolling Retrievers. Tissue Antigens 75(6):684-690.  doi.org/10.1111/j.1399- 0039.2010.01440.x

Kennedy L. 2011. Identifying genetic markers for auto-immune diseases in the dog. Tufts' Canine and Feline Breeding and Genetics Conference, 2011.

Massey J, Boag A, Short AD, Scholey RA, Henthorn PS, Littman MP, Husebye E, Catchpole B, Pedersen N, Mellersh CS, Ollier WER, Kennedy LJ. 2013. MHC class II association study in eight breeds of dog with hypoadrenocorticism. Immunogenetics 65: 291-297. doi.org/10.1007/s00251-013-0680-2

Pedersen NC, Brucker L, Tessier NG, Liu H, Penedo MCT, Hughes S, Oberbauer A, Sacks B (2015) The effect of genetic bottlenecks and inbreeding on the incidence of two major autoimmune diseases in Standard Poodles, sebaceous adenitis and Addison’s disease. doi.org/10.1186/s40575-015-0026-5

Treeful AE, AK Rendahl, & SG Friedenberg. 2019. DLA class II haplotypes show sex-specific associations with primary hypoadrenocorticism in Standard Poodle dogs. Immunogenetics (April 2019); doi.org/10.1007/s00251-019-01113-0

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