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post #1 of 11 (permalink) Old 07-23-2019, 10:22 PM Thread Starter
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DCM Update: MAJOR discovery points to autoimmune disease in Dobermans

Some people have suspected this for some time. Where I'm concerned, I couldn't help but shake the notion that genetic diversity (or lack thereof) was the culprit, as well as inbreeding, especially after I started seeing numbers. The big problem is where do we go from here, and do we have enough breeders brave enough to map the uncharted territory the breed will need us to venture into to preserve it?

From the creator of BetterBred (partnered with the VGL at UC Davis):

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An important new paper from Germany now shows something I have long suspected – that dilated cardiomyopathy in Doberman Pinschers is an autoimmune disease. Apparently, Doberman Pinschers with DCM have increased 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.
https://www.betterbred.com/2019/07/2...QKB06al6jVxRkc

Here is the paper:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611557/

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Abstract

Background
Autoimmunity associated with autoantibodies against the β1-adrenergic receptor (β1-AAB) is increasingly accepted as the driver of human dilated cardiomyopathy (DCM). Unfortunately, there is a lack of animal models to extend the knowledge about β1-AAB autoimmunity in DCM and to develop appropriate treatment strategies.

Objectives
To introduce an animal model, we investigated the β1-AAB associated autoimmunity in Doberman Pinscher (DP) with dilated cardiomyopathy, which has similarities to human DCM.

Materials and methods
Eighty-seven DP with cardiomyopathy in terms of pathological ECG and echocardiography (DoCM) and 31 dogs (at enrollment) without DoCM (controls) were analyzed for serum activity of β1-AAB with a bioassay that records the chronotropic response of spontaneously beating cultured neonatal rat cardiomyocytes to the DP’s IgG. To locate the receptor binding site of β1-AAB and the autoantibody’s sensitivity to inhibition, competing experiments with related blockers were performed with the bioassay. In controls that developed DoCM during follow-up, β1-AAB were analyzed during progress.

Results
Fifty-nine (67.8%) DoCM dogs and 19 (61.3%) controls were β1-AAB positive. Of the controls that developed DoCM, 8 were β1-AAB positive (p = 0.044 vs. dogs remaining in the control group); their β1-AAB activity increased with the cardiomyopathy progress (p<0.02). To supplement DoCM group with the 9 animals which developed cardiomyopathy in the follow up, a more pronounced β1-AAB positivity became visible in the DoCM group (p = 0.066).

Total and cardiac mortality were higher in β1-AAB positive DP (p = 0.002; p = 0037). The dogs’ β1-AAB recognized a specific epitope on the second extracellular receptor and were sensitive to inhibition by drugs already successfully tested to inhibit the corresponding human autoantibody.

Conclusions
Doberman Pinschers presented β1-AAB associated autoimmunity, similar as in the pathogenesis of human DCM. Consequently, DP could compensate the lack of animal models for the investigation of β1-AAB autoimmunity in human DCM.
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post #2 of 11 (permalink) Old 07-23-2019, 10:59 PM
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Thanks...

The quote was easy to read and quite understandable.

The abstract, was a bit difficult to interpret. And I have a background in biology.

Still, all seems to make sense.

Isn't that why we (some of us) are testing our dogs early for DCM via echocardiography, 24 hr Holters and full blood panels?

The hope being that an early diagnosis will lead to medical treatment, very similar to what is used in humans, to hopefully put the disease in remission? I had a dog who doubled his initial prognostic life expectancy by early diagnosis and medications.

The autoimmune concept is interesting. Yet I am not quite understanding what the solution would be for breeders. I do really like the fact that the small availability of Doberman investigative models (87 in this study, which is very small) could be augmented by similar studies in humans.

All in all... Fascinating.

Again. Thanks Artemis...

John
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post #3 of 11 (permalink) Old 07-24-2019, 06:54 AM Thread Starter
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Originally Posted by 4x4bike ped View Post
The autoimmune concept is interesting. Yet I am not quite understanding what the solution would be for breeders. I do really like the fact that the small availability of Doberman investigative models (87 in this study, which is very small) could be augmented by similar studies in humans.

All in all... Fascinating.

Again. Thanks Artemis...

John
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I didn't want to post the article and the study in full. But in short, Dobermans are highly highly inbred and have suffered a huge loss in genetic diversity. With that in mind the only way forward is going to be to outcross outside "well-bred" lines for the most part and use unknowns (foreign dogs from countries where neither Europe or North America has used their dogs maybe ever) as well as what we generally consider "less than" or "poorly bred" dogs.

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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.

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.
There are more parallels to be drawn with the Poodle situation, even if Dobermans are in a worse position than Poodles were.

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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 int he 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 co-operation 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.
Which means the solution for Doberman breeders is to retrieve what's left of the diversity in the breed, patiently interbreed high diversity dogs for generations, and use them to outcross to our major lines. (In a nutshell). But is is going to be a challenge - I have seen some breeders say they'd rather let the breed die out if increasing diversity means they have to use dogs from "pet lines".

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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.

It is not an easy one – 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.
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post #4 of 11 (permalink) Old 07-24-2019, 06:58 AM
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I read the actual paper, very interesting (I work on the antibody field). While most of the cases in the study showed the autoimmune biomarker, there were cases that did not.

I would say the statements posted by the BetterBred on that blog are an extrapolation, an interesting hypothesis, but certainly not the only one that can be made based on the paper.
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post #5 of 11 (permalink) Old 07-24-2019, 08:56 AM Thread Starter
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Originally Posted by Dobe_Mom View Post
I read the actual paper, very interesting (I work on the antibody field). While most of the cases in the study showed the autoimmune biomarker, there were cases that did not.

I would say the statements posted by the BetterBred on that blog are an extrapolation, an interesting hypothesis, but certainly not the only one that can be made based on the paper.
I agree, which is why I entitled the thread "points to autoimmune" as opposed to BB's chosen title of "DCM is an automimmune disease".

From all that we can attest, DCM is in all probability a multi-factor disease. I'd even venture to say that based on what we can observe in Dobermans (and now, with diet-induced cases), that there may even be more than one type of DCM. Are we looking at this the wrong way by considering as a single disease?

One good thing is that the connection to DCM in humans may funnel more funding towards research and study in dobermans.
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post #6 of 11 (permalink) Old 07-24-2019, 12:38 PM
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Quote:
Originally Posted by Dobe_Mom View Post
I read the actual paper, very interesting (I work on the antibody field). While most of the cases in the study showed the autoimmune biomarker, there were cases that did not.

I would say the statements posted by the BetterBred on that blog are an extrapolation, an interesting hypothesis, but certainly not the only one that can be made based on the paper.
Thanks for that, Sandra. I always worry about the rush to share things - a lot of it can be so misinterpreted!

Still, I am glad to see continuing research, of course, and I *personally* think that diversity in breeding is really important.


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post #7 of 11 (permalink) Old 07-24-2019, 07:32 PM
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This is an interesting article (received it in my inbox today), and I very much support what the Better Bred folks are doing and discussing. It's not an outlandish hypothesis. With extreme inbreeding, it seems like the immune system is one of the first things to be disrupted, no surprises there, but the possibility of a link between an autoimmune disorder and DCM is quite interesting. I'm quite hopeful in my confirmation bias with this, time and additional research will presumably provide a conclusive answer one way or the other.

FWIW, Kira is an outlier, probably one of those extreme outliers who the researchers would've wanted photos of due to doubts that she's really a Doberman. All it apparently took was (1) Not a lot of inbreeding even in the '70s and '80s show lines from her pedigree and (2) A 30-or-40-year break from show line breeding antics such as inbreeding and popular sire fads. Beyond that, she's not an outlier because of exotic bloodlines or anything, as far back as her extended pedigree goes, it all seems to be Canadian and US lines.

The real tragedy is that I don't believe that she is truly an outlier. She's probably just in the silent majority of Dobermans that all breeders ignore and folks on the breed-specific forums stare down their noses at. The folks getting the VGL diversity tests are folks who I honestly believe care enough about improving the health of the breed to spend the money and invest the time, but they're part of a culture which has been entrenched in bad practices for a long, long time, and one population is overrepresented as a result. I would bet the amount of money I paid for Kira that not a single one of her siblings from the 3 or so litters her dam produced has had a swab submitted for the purpose of the diversity test. Is an animal a "genetic outlier" simply because it's underrepresented in a study because most of the owners of its relatives are oblivious to the problems plaguing the breed? The thing that I see as tragic is that there are folks whose intentions are good, they are trying their best, but they are trapping themselves in the largely futile effort of attempting to recover genetic diversity from an extremely inbred population.

They're really out there, I guarantee if folks put aside some of the bias favoring "reputable breeders" and titles, and uses a very critical eye when evaluating animals from the silent majority of farm folks and the less-shady BYBs, there are gems to be found. Just don't throw common sense out the window. If a breeder is clearly motivated by greed and not the well-being of their animals or the breed as a whole, move along to the next. If a breeder clearly has little intelligence involved in their choices (breeding z-factor Dobes, convenient/pointless linebreeding, being obsessed with the monetary value of "rare" coloration and such), move along. If a breeder is trying to break-into the fancy named bloodline/kennels game to give themselves more credibility in their endeavors or to make more money on someone else's brand, move along. There will be a few breeders left who probably won't come close to sweeping all the boxes on a Reputable Breeder Checklist, but they'll have avoided enough of the wrong things that the pups they produce are correct enough, and have some of those time capsule genetic outlier genes.

It's a shame that, as Artemis mentions, some breeders are so full of themselves and bizarre bloodline royalty notions that they'd sooner let a breed die out than go slumming, but it's a good thing that they will mostly only hurt themselves and the other bloodline/show-ribbon snobs. There are a few breeders on here I consider to be extremely promising in terms of using off-the-beaten-path bloodlines despite getting ripped-on for their efforts, and they will hopefully keep the Doberman breed on the rails, too. Well, them and the folks like me who have no problem going slumming and are completely unapologetic for doing so.
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post #8 of 11 (permalink) Old 07-25-2019, 07:56 AM
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I agree. The snobby approach is proven not to work...we humans proved that with our royal bloodlines. They, at one time were great, or they would not have gotten in that position to begin with. Then, at the end, just due to the snob mentality produced blithering idiots that "thought" they were superior due to bloodline and looks alone.

I am a function over form guy myself. To me, moving the breeds disposition back to what the breed was intentionally bred for would be more of an homage to Von Dobermann. Form can always follow and more easily done.
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I agree. The snobby approach is proven not to work...we humans proved that with our royal bloodlines. They, at one time were great, or they would not have gotten in that position to begin with. Then, at the end, just due to the snob mentality produced blithering idiots that "thought" they were superior due to bloodline and looks alone.

I am a function over form guy myself. To me, moving the breeds disposition back to what the breed was intentionally bred for would be more of an homage to Von Dobermann. Form can always follow and more easily done.
His name was just Dobermann. No von lol. Karl Friedrich Louis Dobermann. Ironically "von" in surnames is associated to nobility. (It meaning "of")
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post #10 of 11 (permalink) Old 07-26-2019, 09:22 AM
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His name was just Dobermann. No von lol. Karl Friedrich Louis Dobermann. Ironically "von" in surnames is associated to nobility. (It meaning "of")
Thanks for the correction. I always thought there was a Von in there for some reason. Oh well. You got my drift. I still stand by my statement...lol

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post #11 of 11 (permalink) Old 07-27-2019, 02:10 AM
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Originally Posted by kaloric View Post

FWIW, Kira is an outlier, probably one of those extreme outliers who the researchers would've wanted photos of due to doubts that she's really a Doberman. All it apparently took was (1) Not a lot of inbreeding even in the '70s and '80s show lines from her pedigree and (2) A 30-or-40-year break from show line breeding antics such as inbreeding and popular sire fads. Beyond that, she's not an outlier because of exotic bloodlines or anything, as far back as her extended pedigree goes, it all seems to be Canadian and US lines.

The real tragedy is that I don't believe that she is truly an outlier. She's probably just in the silent majority of Dobermans that all breeders ignore and folks on the breed-specific forums stare down their noses at. The folks getting the VGL diversity tests are folks who I honestly believe care enough about improving the health of the breed to spend the money and invest the time, but they're part of a culture which has been entrenched in bad practices for a long, long time, and one population is overrepresented as a result. I would bet the amount of money I paid for Kira that not a single one of her siblings from the 3 or so litters her dam produced has had a swab submitted for the purpose of the diversity test. Is an animal a "genetic outlier" simply because it's underrepresented in a study because most of the owners of its relatives are oblivious to the problems plaguing the breed? The thing that I see as tragic is that there are folks whose intentions are good, they are trying their best, but they are trapping themselves in the largely futile effort of attempting to recover genetic diversity from an extremely inbred population.

They're really out there, I guarantee if folks put aside some of the bias favoring "reputable breeders" and titles, and uses a very critical eye when evaluating animals from the silent majority of farm folks and the less-shady BYBs, there are gems to be found. Just don't throw common sense out the window. If a breeder is clearly motivated by greed and not the well-being of their animals or the breed as a whole, move along to the next. If a breeder clearly has little intelligence involved in their choices (breeding z-factor Dobes, convenient/pointless linebreeding, being obsessed with the monetary value of "rare" coloration and such), move along. If a breeder is trying to break-into the fancy named bloodline/kennels game to give themselves more credibility in their endeavors or to make more money on someone else's brand, move along. There will be a few breeders left who probably won't come close to sweeping all the boxes on a Reputable Breeder Checklist, but they'll have avoided enough of the wrong things that the pups they produce are correct enough, and have some of those time capsule genetic outlier genes.

It's a shame that, as Artemis mentions, some breeders are so full of themselves and bizarre bloodline royalty notions that they'd sooner let a breed die out than go slumming, but it's a good thing that they will mostly only hurt themselves and the other bloodline/show-ribbon snobs. There are a few breeders on here I consider to be extremely promising in terms of using off-the-beaten-path bloodlines despite getting ripped-on for their efforts, and they will hopefully keep the Doberman breed on the rails, too. Well, them and the folks like me who have no problem going slumming and are completely unapologetic for doing so.
I believe Kira and Juneau have similar stats in BB. I agree that I don't really think outliers are much of outliers at all. Thank you.
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