DCM in Dobermans is an autoimmune disease

An important new paper from Germany now shows something I have long suspected – that dilated cardiomyopathy in Doberman Pinschers includes an autoimmune mechanism. Apparently, Doberman Pinschers with DCM can have increased levels of autoantibodies against the Beta1-adrenergic receptor – a specific protein crucial to cardiac function that is involved in activating cellular responses. Not only does this paper offer potential progress in treatment, it may offer breeders insight that can help them lessen the frequency of this disease in the breed.

While researchers have searched long and hard for a single causative gene, or two or more, in the nearly three years since I became aware of the devastation of DCM in Dobermans, I have been unable to shake a sense of déjà vu. The reactions of breeders I’ve witnessed have much in common with the experiences of Standard Poodle breeders and our search for causes of breed specific autoimmune diseases in our own breed.

From early educated guesses on mode of inheritance to the disease appearing in almost any litter, to breeders begging for news from various researchers who seemed so sure they’d find something, to the wait for actionable information – the process is excruciating. Meanwhile breeders don’t know quite what to do with their breeding stock but breed their healthiest dogs and hope for the best. As was true in Standard Poodles, there is a small minority of breeders suggesting that breed-wide inbreeding in Dobermans could be the culprit, but there seems to be much resistance to the idea from many serious breeders. It has long been possible to show overall lower longevity with an increase in inbreeding using pedigree based statistics, but breeders often aren’t sure of this until they are several generations down the line. After all, linebreeding is a powerful tool for increasing predictability of desirable traits. When used wisely, it has clear benefits – when overused, it can cause lasting harm.

In Standard Poodles we were able to make a direct connection between the breed’s major genetic bottleneck and higher rates of autoimmune disease – and subsequent whole genome sequencing by another team independently confirmed that the most troublesome breed specific disease, Addison’s or hypoadrenocorticism, was not due to a single causative gene.

The study by noted Doberman researcher Dr Gerard Wess and his team shows clearly an autoantibody at work in a large cohort of Doberman Pinschers.

So when we got the first analysis of the Doberman gene pool back from Dr Pedersen, it was shocking – but not surprising. The breed is more inbred than either Standard Poodles or Italian Greyhounds, both of which have significant autoimmune disease associated with historical inbreeding and loss of diversity. Out of all the breeds in the BetterBred database, the Dobermans have the highest fixation index, the lowest effective alleles per locus, the highest average Internal Relatedness, the lowest average Outlier Index and the most extreme Average Genetic Relatedness (which is what happens to this measure when a breed is more inbred). What’s more, the limited number and lopsided distribution of DLA haplotypes in the breed supports an autoimmune pathogenesis for DCM. 78% of all Class II DLA haplotypes in the breed are a single variant – and 76% of Class I DLA haplotypes are a single haplotype. Of the 508 Dobermans in the Betterbred database, 59.4% or 302 dogs are homozygous for these two DLA haplotypes – meaning they are identical at over 2 million base pairs of DLA. Of the remaining 204 dogs, 166 are heterozygous for those two DLA haplotypes and only 38 dogs in the database do not have them. That shows an alarming diminishment of healthy biodiversity in the region of the DNA that controls immune function.

So why wouldn’t Dobermans have similar outcomes as these other breeds with severe bottlenecks? They suffer, too, from autoimmune thyroiditis, and chronic active hepatitis – an autoimmune condition – plus cancer and bloat. But their biggest killer is DCM. I wondered then if it was autoimmune related – an autoimmune cardiac myositis of sorts. But I found nothing at the time in the literature to that effect.

Until now. The study by noted Doberman researcher Dr Gerard Wess and his team shows clearly an autoantibody at work in a large cohort of Doberman Pinschers. His focus is on whether this makes the Doberman an ideal candidate for being a human model for DCM, which has already been shown in some cases to be autoimmune-related. His conclusion is yes.

What we breeders can take from this is similar to what we have learned in the aforementioned breeds. By maximizing diversity, both genome wide and in the DLA, and avoiding the historical inbreeding in the breed as much as possible using carefully planned breeding to genetic outliers, we should be able to lower risk for autoimmune disease. So far in Standard Poodles, the statistics revealed in the huge 2015 study have held true.

This is perhaps the best new news for Doberman breeders world wide in a long time.

By maximizing diversity, both genome wide and in the DLA, and avoiding the historical inbreeding in the breed as much as possible using carefully planned breeding to genetic outliers, we should be able to lower risk for autoimmune disease. So far in Standard Poodles, the statistics revealed in the huge 2015 study have held true.

Until recently, having viewed hundreds of DNA profiles of Doberman Pinschers from around the world, I had also despaired that perhaps there’s no diversity left in Dobermans – no unrelated dogs left in the breed. Perhaps all the lines are now far too similar and genetically related and the breed is therefore stuck with these disastrous outcomes or they must outcross to another breed – something no purebred breeder wants to have to do.

But last week, a Doberman aficionado in Washington state who was able to test a number of obscure pet bred dogs got results back. These dogs are in fact such genetic outliers, so extremely different in genetic data from the hundreds of Dobermans we’ve seen, that I wanted to see pictures to be sure they are purebred. Based on their pictures, there is no reason to believe they are anything but Dobermans. They may not be as handsome as many we see in show ring, but they are not terrible, and they are mostly living long lives with little to no heart disease. This is anecdotal entirely of course. We don’t actually know enough about these dogs and their pedigrees via documented evidence – but it gave me some hope for the breed.

For over 15 years Standard Poodle breeders have been quietly finding ways to rehabilitate old, obscure lines of Standard Poodles by finding them, using the best dogs from them possible, health testing and improving these dogs – all in an attempt to preserve any old existing genetics left from the original breed that had somehow escaped the dominant genetic bottleneck. There really were only a handful of lines, and a few worthwhile dogs from each line. Only a few made the cut. When they started out, the breeders who sought out these genetic outliers knew it would be controversial, and pursued their efforts quietly. The cooperation grew, and soon there were many breeders involved, all reporting on health outcomes and type and temperament. Some used Miniature Poodles to find more diversity (intervariety Poodles can be registered with the AKC, though not in Europe or in UKC) and other used various combinations of the few unusual dogs we found in Russia, the Czech Republic, England, France, and here in obscure areas of the US and Canada. Some of those lines, sadly, flunked out. Some of them simply lacked too much type. But some of them offered a lot in the way of both structure and health that had been lost to the severe genetic bottleneck in the breed.

By 2014 when we tested a huge cohort of Standard Poodles with UC Davis, it was clear that descendants of those few salvaged lines contained about 70% of the diversity existent in the breed, even though they were only 30% of the dogs tested.

All of this is to say: if Doberman breeders want to lower their risks for DCM, there is a road map toward better health and less disease: find more of the existing diversity in the breed and distribute it better. And while you are doing that, do not promote further loss of existing diversity by continuing to breed toward the current genetic bottleneck.

One note of caution – this cannot be done by selecting only the least inbred, homozygous or low “genetic COI” matings. Because there are so few unusual dogs in the breed, if these dogs are bred to minimize inbreeding only without care for selecting mates that are not highly related to the rest of the breed, they will be bred to very common dogs, which will only make their offspring more common than themselves and therefore at greater risk.

This is not an easy task. It’s not a pass to breed poorly bred dogs though some may fear it is, it can’t easily be done without criticism, outcry and heartbreak because it’s a different way forward – but it could save the breed. All that’s necessary is a few courageous breeders and a few highly experienced breed experts willing to try.

What’s more, we now have the genetic tools available to us that were actually designed for this purpose – everything we do at BetterBred started with and is based on the combined experience and needs of the breeders who helped restore and continue to manage the Standard Poodle gene pool.

One note of caution – this cannot be done by selecting only the least inbred, homozygous or low “genetic COI” matings. Because there are so few unusual dogs in the breed, if these dogs are bred to minimize inbreeding only without care for selecting mates that are not highly related to the rest of the breed, they will be bred to very common dogs, which will only make their offspring more common than themselves and therefore at greater risk. Outliers must be bred to the least related available outliers in order to increase the frequency of the unusual genetics in the breed. It’s been done to excellent effect in Standard Poodles – and as Dr. Niels Pedersen has said, it didn’t take a few generations to get the breed into its current state, and it will take a number of generations to get it out. Now, however, there’s a good place to start.

So that’s why I’m so excited to have read this new paper – and while there is often much bad news in Dobermans – I see a glimmer of hope on the horizon.

*Addendum: This post was written not as a thorough review or critique of Dr. Wess’ research, but rather to highlight the incentive and importance for breeders to mitigate effects of severe genetic bottlenecks like the one in the Doberman breed. This is of particular interest in relation to Doberman DCM because, in addition to other deleterious effects of historical inbreeding, genetic bottlenecks have been associated with autoimmune disease in a number of other breeds. Dr Wess’ study is the first view of this autoimmune mechanism in the most common and alarming killer of Dobermans. Autoimmune diseases vary widely and most have varying unique additional genetic factors and triggers that require additional research to understand. It would be unwise for breeders and lovers of Dobermans to dismiss these initial findings outright simply because it is new. Dr Wess has published extensively on cardiomyopathy in dogs and no less than 15 studies on Dobermans in particular. Other extensive, well-funded research on DCM in Dobermans has not offered breeders much help in preventing or lowering frequency of the disease in the breed. Dr Wess’ research is both careful and persuasive, his knowledge of the breed is extensive, and he states clearly that while autoimmunity is not the sole cause of DCM in Dobermans, autoimmunity appears to be involved in disease progression and is statistically significantly higher in the dogs that died during the study. “Total and cardiac mortality were higher in β1-AAB positive DP (p = 0.002; p = 0037).” Moreover Wess states “..we assume a prominent driving role for β1-AAB associated autoimmunity in the pathogenesis of Doberman cardiomyopathy, as is increasingly being accepted for human DCM.” While breeders wait for independent replication of this research, there is no reason to ignore its potential.