A Novel Locus for Dilated Cardiomyopathy, Diffuse Myocardial Fibrosis, and Sudden Death on Chromosome 10q25-26

Ellinor, Patrick T.; Klaassen, Sabine; Probst, Susanne; Gerull, Brenda; Shin, Jordan T.; Toeppel, Andrea; Heuser, Arnd; Michely, Beate; Yoerger, Danita M.; Song, Bong-Seok; Pilz, Bernhard; Krings, Gregor; Coplin, Bruce; Lange, Peter; Dec, G. William; Hennies, Hans Christian; Thierfelder, Ludwig; MacRae, Calum A.

doi:10.1016/j.jacc.2006.01.079

Cited by 33 publications

(22 citation statements)

References 39 publications

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“…We explored whether the loci we identified overlap with human GWAS results by examining the top twelve previously identified significant and suggestive human loci 6,7,37 . The human loci were mapped onto the mouse genome using the NCBI Homologene resource and compared to a set of loci identified for the weight traits based on a slightly relaxed stringency (P<1E-05, MAF>5%) from the HMDP study.…”

Section: Resultsmentioning

confidence: 99%

Mapping Genetic Contributions to Cardiac Pathology Induced by Beta-Adrenergic Stimulation in Mice

Rau

Wang

Avetisyan

et al. 2015

Circ Cardiovasc Genet

128

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Background Chronic stress-induced cardiac pathology exhibits both a wide range in severity and a high degree of heterogeneity in clinical manifestation in human patients. This variability is contributed to by complex genetic and environmental etiologies within the human population. Genetic approaches to elucidate the genetics underlying the acquired forms of cardiomyopathies, including genome-wide association studies (GWAS), have been largely unsuccessful, resulting in limited knowledge as to the contribution of genetic variations for this important disease. Methods and Results Using the β-adrenergic agonist isoproterenol as a specific pathological stressor to circumvent the problem of etiological heterogeneity, we performed a GWAS for genes influencing cardiac hypertrophy and fibrosis in a large panel of inbred mice. Our analyses revealed 7 significant loci and 17 suggestive loci, containing an average of 14 genes, affecting cardiac hypertrophy, fibrosis and surrogate traits relevant to HF. Several loci contained candidate genes which are known to contribute to Mendelian cardiomyopathies in humans or have established roles in cardiac pathology based on molecular or genetic studies in mouse models. In particular, we identify Abcc6 as the gene underlying a fibrosis locus by validating that an allele with a splice mutation of Abcc6 dramatically and rapidly promotes isoproterenol induced cardiac fibrosis. Conclusions Genetic variants significantly contribute to the phenotypic heterogeneity of stress induced cardiomyopathy. Systems genetics is an effective approach to identify genes and pathways underlying the specific pathological features of cardiomyopathies. Abcc6 is a previously unrecognized player in the development of stress-induced cardiac fibrosis.

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Section: Resultsmentioning

confidence: 99%

Mapping Genetic Contributions to Cardiac Pathology Induced by Beta-Adrenergic Stimulation in Mice

Rau

Wang

Avetisyan

et al. 2015

Circ Cardiovasc Genet

128

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“…The phenotype was associated with a locus on chromosome 10q2-26, a region that included the BAG3 gene [13]. Two mutations in BAG3 were subsequently identified in Japanese patients with familial dilated cardiomyopathy (Arg218Trp and Leu462Pro).…”

Section: Bag3 Mutants Myofibrillar Myopathy and Dilated Cardiomyopathymentioning

confidence: 99%

BAG3: a new player in the heart failure paradigm

et al. 2015

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BAG3 is a cellular protein that is expressed predominantly in skeletal and cardiac muscle but can also be found in the brain and in the peripheral nervous system. BAG3 functions in the cell include: serving as a co-chaperone with members of the heat-shock protein family of proteins to facilitate the removal of misfolded and degraded proteins, inhibiting apoptosis by interacting with Bcl2 and maintaining the structural integrity of the Z-disk in muscle by binding with CapZ. The importance of BAG3 in the homeostasis of myocytes and its role in the development of heart failure was evidenced by the finding that single allelic mutations in BAG3 were associated with familial dilated cardiomyopathy. Furthermore, significant decreases in the level of BAG3 have been found in end-stage failing human heart and in animal models of heart failure including mice with heart failure secondary to trans-aortic banding and in pigs after myocardial infarction. Thus, it becomes relevant to understand the cellular biology and molecular regulation of BAG3 expression in order to design new therapies for the treatment of patients with both hereditary and non-hereditary forms of dilated cardiomyopathy.

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“…Myocardial fibrosis consistently is associated with sudden death in human cardiomyopathies, including DCM, hypertrophic cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy. It has been hypothesized that this may result from the effects of fibrosis on myocardial electrical inhomogeneity or the association of fibrosis with abnormal intramyocardial coronary arterioles [4].…”

Section: Discussionmentioning

confidence: 99%

Myocardial tumor necrosis factor-alpha expression in a sudden death due to dilated cardiomyopathy with endomyoelastofibrosis

Riezzo

Pomara

Neri

et al. 2009

International Journal of Cardiology

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A Novel Locus for Dilated Cardiomyopathy, Diffuse Myocardial Fibrosis, and Sudden Death on Chromosome 10q25-26

Abstract: We have mapped a novel locus for cardiomyopathy, diffuse myocardial fibrosis, and sudden death to chromosome 10q25-q26. The identification of the causative gene in this interval will be an important step in understanding the fundamental mechanisms of heart failure and sudden death.

Cited by 33 publications

References 39 publications

Mapping Genetic Contributions to Cardiac Pathology Induced by Beta-Adrenergic Stimulation in Mice

Mapping Genetic Contributions to Cardiac Pathology Induced by Beta-Adrenergic Stimulation in Mice

BAG3: a new player in the heart failure paradigm

Myocardial tumor necrosis factor-alpha expression in a sudden death due to dilated cardiomyopathy with endomyoelastofibrosis

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