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A locus on chromosome 5 is associated with dilated cardiomyopathy in Doberman Pinschers.

ABSTRACT: Dilated cardiomyopathy (DCM) is a heterogeneous group of heart diseases with a strong genetic background. Currently, many human DCM cases exist where no causative mutation can be identified. DCM also occurs with high prevalence in several large dog breeds. In the Doberman Pinscher a specific DCM form characterized by arrhythmias and/or echocardiographic changes has been intensively studied by veterinary cardiologists. We performed a genome-wide association study in Doberman Pinschers. Using 71 cases and 70 controls collected in Germany we identified a genome-wide significant association to DCM on chromosome 5. We validated the association in an independent cohort collected in the United Kingdom. There is no known DCM candidate gene under the association signal. Therefore, DCM in Doberman Pinschers offers the chance of identifying a novel DCM gene that might also be relevant for human health.

SUBMITTER: Mausberg TB

PROVIDER: S-EPMC3098859 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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A locus on chromosome 5 is associated with dilated cardiomyopathy in Doberman Pinschers.

Mausberg Theresa-Bernadette TB Wess Gerhard G Simak Julia J Keller Lisa L Drögemüller Michaela M Drögemüller Cord C Webster Matthew T MT Stephenson Hannah H Dukes-McEwan Joanna J Leeb Tosso T

PloS one 20110520 5

Dilated cardiomyopathy (DCM) is a heterogeneous group of heart diseases with a strong genetic background. Currently, many human DCM cases exist where no causative mutation can be identified. DCM also occurs with high prevalence in several large dog breeds. In the Doberman Pinscher a specific DCM form characterized by arrhythmias and/or echocardiographic changes has been intensively studied by veterinary cardiologists. We performed a genome-wide association study in Doberman Pinschers. Using 71 c ...[more]

PMID: 21625443

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Project description:BackgroundAutoimmunity 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.ObjectivesTo 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 methodsEighty-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.ResultsFifty-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.ConclusionsDoberman 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.

Dataset Information

A locus on chromosome 5 is associated with dilated cardiomyopathy in Doberman Pinschers.

Publications

A locus on chromosome 5 is associated with dilated cardiomyopathy in Doberman Pinschers.

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