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The Genetic Architecture of Carbon Tetrachloride-Induced Liver Fibrosis in Mice.
Tuominen, Iina; Fuqua, Brie K; Pan, Calvin; Renaud, Nicole; Wroblewski, Kevin; Civelek, Mete; Clerkin, Kara; Asaryan, Ashot; Haroutunian, Sara G; Loureiro, Joseph; Borawski, Jason; Roma, Guglielmo; Knehr, Judith; Carbone, Walter; French, Samuel; Parks, Brian W; Hui, Simon T; Mehrabian, Margarete; Magyar, Clara; Cantor, Rita M; Ukomadu, Chinweike; Lusis, Aldons J; Beaven, Simon W.
Afiliación
  • Tuominen I; Department of Medicine, Vatche and Tamar Manoukian Division of Digestive Diseases at UCLA and Pfleger Liver Institute, David Geffen School of Medicine at UCLA, Los Angeles, California.
  • Fuqua BK; Departments of Medicine, Microbiology and Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California.
  • Pan C; Departments of Medicine, Microbiology and Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California.
  • Renaud N; Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
  • Wroblewski K; Department of Medicine, Vatche and Tamar Manoukian Division of Digestive Diseases at UCLA and Pfleger Liver Institute, David Geffen School of Medicine at UCLA, Los Angeles, California.
  • Civelek M; Departments of Medicine, Microbiology and Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California.
  • Clerkin K; Department of Medicine, Vatche and Tamar Manoukian Division of Digestive Diseases at UCLA and Pfleger Liver Institute, David Geffen School of Medicine at UCLA, Los Angeles, California.
  • Asaryan A; Department of Medicine, Vatche and Tamar Manoukian Division of Digestive Diseases at UCLA and Pfleger Liver Institute, David Geffen School of Medicine at UCLA, Los Angeles, California.
  • Haroutunian SG; Department of Medicine, Vatche and Tamar Manoukian Division of Digestive Diseases at UCLA and Pfleger Liver Institute, David Geffen School of Medicine at UCLA, Los Angeles, California.
  • Loureiro J; Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
  • Borawski J; Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
  • Roma G; Novartis Pharma AG, Basel, Switzerland.
  • Knehr J; Novartis Pharma AG, Basel, Switzerland.
  • Carbone W; Novartis Pharma AG, Basel, Switzerland.
  • French S; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.
  • Parks BW; Departments of Medicine, Microbiology and Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California.
  • Hui ST; Departments of Medicine, Microbiology and Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California.
  • Mehrabian M; Departments of Medicine, Microbiology and Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California.
  • Magyar C; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.
  • Cantor RM; Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California.
  • Ukomadu C; Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
  • Lusis AJ; Departments of Medicine, Microbiology and Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California. Electronic address: jlusis@mednet.ucla.edu.
  • Beaven SW; Department of Medicine, Vatche and Tamar Manoukian Division of Digestive Diseases at UCLA and Pfleger Liver Institute, David Geffen School of Medicine at UCLA, Los Angeles, California. Electronic address: sbeaven@mednet.ucla.edu.
Cell Mol Gastroenterol Hepatol ; 11(1): 199-220, 2021.
Article en En | MEDLINE | ID: mdl-32866618
BACKGROUND & AIMS: Liver fibrosis is a multifactorial trait that develops in response to chronic liver injury. Our aim was to characterize the genetic architecture of carbon tetrachloride (CCl4)-induced liver fibrosis using the Hybrid Mouse Diversity Panel, a panel of more than 100 genetically distinct mouse strains optimized for genome-wide association studies and systems genetics. METHODS: Chronic liver injury was induced by CCl4 injections twice weekly for 6 weeks. Four hundred thirty-seven mice received CCl4 and 256 received vehicle, after which animals were euthanized for liver histology and gene expression. Using automated digital image analysis, we quantified fibrosis as the collagen proportionate area of the whole section, excluding normal collagen. RESULTS: We discovered broad variation in fibrosis among the Hybrid Mouse Diversity Panel strains, demonstrating a significant genetic influence. Genome-wide association analyses revealed significant and suggestive loci underlying susceptibility to fibrosis, some of which overlapped with loci identified in mouse crosses and human population studies. Liver global gene expression was assessed by RNA sequencing across the strains, and candidate genes were identified using differential expression and expression quantitative trait locus analyses. Gene set enrichment analyses identified the underlying pathways, of which stellate cell involvement was prominent, and coexpression network modeling identified modules associated with fibrosis. CONCLUSIONS: Our results provide a rich resource for the design of experiments to understand mechanisms underlying fibrosis and for rational strain selection when testing antifibrotic drugs.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tetracloruro de Carbono / Predisposición Genética a la Enfermedad / Redes Reguladoras de Genes / Hígado / Cirrosis Hepática Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Cell Mol Gastroenterol Hepatol Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tetracloruro de Carbono / Predisposición Genética a la Enfermedad / Redes Reguladoras de Genes / Hígado / Cirrosis Hepática Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Cell Mol Gastroenterol Hepatol Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos