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
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DOI：
10.1161/circgenetics.113.000732
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发表时间：
2015-02-01
影响因子：
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通讯作者：
Lusis, Aldons J.
中科院分区：
文献类型：
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作者：
Rau, Christoph D.;Wang, Jessica;Lusis, Aldons J.
背景-慢性应激诱导的心脏病理在人类患者的临床表现中表现出广泛的严重程度和高度的异质性。这种变异性是由人群中复杂的遗传和环境病因学造成的。阐明获得性心肌病的遗传学基础的遗传学方法，包括全基因组关联研究，在很大程度上是不成功的，导致对这种重要疾病的遗传变异的贡献的知识有限。方法和结果-使用β-肾上腺素能激动剂异丙肾上腺素作为特定的病理应激源来规避病因异质性的问题，我们在一组大的近交系小鼠中对影响心脏肥大和纤维化的基因进行了全基因组关联研究。我们的分析揭示了7个显著位点和17个暗示位点，平均包含14个基因，影响心脏肥大、纤维化和与心力衰竭相关的替代性状。几个基因座含有已知导致人类孟德尔心肌病的候选基因，或者基于小鼠模型中的分子或遗传研究在心脏病理学中具有确定的作用。特别是，我们确定Abcc 6作为一个新的基因基础的纤维化位点，通过验证，一个等位基因与Abcc 6剪接突变显着，迅速促进异丙肾上腺素诱导的心脏fibrosis. Conclusions遗传变异显着有助于应激诱导的心肌病的表型异质性。系统遗传学是一种有效的方法，以确定基因和途径的具体病理特征的心肌病。Abcc 6是以前未被认识到的应激诱导的心脏纤维化发展的参与者。
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, have been largely unsuccessful, resulting in limited knowledge as to the contribution of genetic variations for this important disease.Methods and Results-Using the beta-adrenergic agonist isoproterenol as a specific pathological stressor to circumvent the problem of etiologic heterogeneity, we performed a genome-wide association study 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 heart failure. 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 a novel 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.