Addison's disease and those doggone DLAs

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 (Massey et al. 2013....).

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 reduce the frequency of haplotype 1 in the population by selective breeding that increases the frequency of other DLA haplotypes could result in an increased frequency of some other expression of 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 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

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

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

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

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

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​

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