title: Mapping genetic contributions to cardiac pathology induced by Beta-adrenergic stimulation in mice.
abstract: 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.
  
  
  RESULTS
  Using the β-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.
authors.affiliation: From the Department of Microbiology, Immunology and Molecular Genetics, Department of Human Genetics (C.D.R., R.A., M.R., A.J.L.), Department of Medicine, Division of Cardiology, David Geffen School of Medicine (J.W., L.M., A.J.L.), and Departments of Anesthesiology, Physiology, and Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine (S.R., Y.W.), University of California, Los Angeles, CA.
authors.forename: Christoph D
authors.initials: CD
authors.lastname: Rau
authors.affiliation: From the Department of Microbiology, Immunology and Molecular Genetics, Department of Human Genetics (C.D.R., R.A., M.R., A.J.L.), Department of Medicine, Division of Cardiology, David Geffen School of Medicine (J.W., L.M., A.J.L.), and Departments of Anesthesiology, Physiology, and Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine (S.R., Y.W.), University of California, Los Angeles, CA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Wang
authors.affiliation: From the Department of Microbiology, Immunology and Molecular Genetics, Department of Human Genetics (C.D.R., R.A., M.R., A.J.L.), Department of Medicine, Division of Cardiology, David Geffen School of Medicine (J.W., L.M., A.J.L.), and Departments of Anesthesiology, Physiology, and Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine (S.R., Y.W.), University of California, Los Angeles, CA.
authors.forename: Rozeta
authors.initials: R
authors.lastname: Avetisyan
authors.affiliation: From the Department of Microbiology, Immunology and Molecular Genetics, Department of Human Genetics (C.D.R., R.A., M.R., A.J.L.), Department of Medicine, Division of Cardiology, David Geffen School of Medicine (J.W., L.M., A.J.L.), and Departments of Anesthesiology, Physiology, and Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine (S.R., Y.W.), University of California, Los Angeles, CA.
authors.forename: Milagros C
authors.initials: MC
authors.lastname: Romay
authors.affiliation: From the Department of Microbiology, Immunology and Molecular Genetics, Department of Human Genetics (C.D.R., R.A., M.R., A.J.L.), Department of Medicine, Division of Cardiology, David Geffen School of Medicine (J.W., L.M., A.J.L.), and Departments of Anesthesiology, Physiology, and Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine (S.R., Y.W.), University of California, Los Angeles, CA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Martin
authors.affiliation: From the Department of Microbiology, Immunology and Molecular Genetics, Department of Human Genetics (C.D.R., R.A., M.R., A.J.L.), Department of Medicine, Division of Cardiology, David Geffen School of Medicine (J.W., L.M., A.J.L.), and Departments of Anesthesiology, Physiology, and Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine (S.R., Y.W.), University of California, Los Angeles, CA.
authors.forename: Shuxun
authors.initials: S
authors.lastname: Ren
authors.affiliation: From the Department of Microbiology, Immunology and Molecular Genetics, Department of Human Genetics (C.D.R., R.A., M.R., A.J.L.), Department of Medicine, Division of Cardiology, David Geffen School of Medicine (J.W., L.M., A.J.L.), and Departments of Anesthesiology, Physiology, and Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine (S.R., Y.W.), University of California, Los Angeles, CA. jlusis@mednet.ucla.edu yibinwang@mednet.ucla.edu.
authors.forename: Yibin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the Department of Microbiology, Immunology and Molecular Genetics, Department of Human Genetics (C.D.R., R.A., M.R., A.J.L.), Department of Medicine, Division of Cardiology, David Geffen School of Medicine (J.W., L.M., A.J.L.), and Departments of Anesthesiology, Physiology, and Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine (S.R., Y.W.), University of California, Los Angeles, CA. jlusis@mednet.ucla.edu yibinwang@mednet.ucla.edu.
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
mesh_terms: D000318:Adrenergic beta-Agonists / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D002874:Chromosome Mapping; D005260:Female; D005355:Fibrosis; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D007545:Isoproterenol / Q000009:adverse effects* / Q000494:pharmacology; D051379:Mice
chemical_list: D000318:Adrenergic beta-Agonists; D007545:Isoproterenol
keywords: catecholamine; genome-wide association scan; genomics; heart failure; mouse