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Genetics of myocardial interstitial fibrosis in the human heart and association with disease.
Nauffal, Victor; Di Achille, Paolo; Klarqvist, Marcus D R; Cunningham, Jonathan W; Hill, Matthew C; Pirruccello, James P; Weng, Lu-Chen; Morrill, Valerie N; Choi, Seung Hoan; Khurshid, Shaan; Friedman, Samuel F; Nekoui, Mahan; Roselli, Carolina; Ng, Kenney; Philippakis, Anthony A; Batra, Puneet; Ellinor, Patrick T; Lubitz, Steven A.
Afiliación
  • Nauffal V; Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA.
  • Di Achille P; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Klarqvist MDR; Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Cunningham JW; Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Hill MC; Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA.
  • Pirruccello JP; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Weng LC; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Morrill VN; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
  • Choi SH; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Khurshid S; Cardiology Division, Massachusetts General Hospital, Boston, MA, USA.
  • Friedman SF; Division of Cardiology, University of California San Francisco, San Francisco, CA, USA.
  • Nekoui M; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Roselli C; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
  • Ng K; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Philippakis AA; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Batra P; Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Ellinor PT; Demoulas Center for Cardiac Arrhythmias, Massachusetts General Hospital, Boston, MA, USA.
  • Lubitz SA; Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Nat Genet ; 55(5): 777-786, 2023 05.
Article en En | MEDLINE | ID: mdl-37081215
ABSTRACT
Myocardial interstitial fibrosis is associated with cardiovascular disease and adverse prognosis. Here, to investigate the biological pathways that underlie fibrosis in the human heart, we developed a machine learning model to measure native myocardial T1 time, a marker of myocardial fibrosis, in 41,505 UK Biobank participants who underwent cardiac magnetic resonance imaging. Greater T1 time was associated with diabetes mellitus, renal disease, aortic stenosis, cardiomyopathy, heart failure, atrial fibrillation, conduction disease and rheumatoid arthritis. Genome-wide association analysis identified 11 independent loci associated with T1 time. The identified loci implicated genes involved in glucose transport (SLC2A12), iron homeostasis (HFE, TMPRSS6), tissue repair (ADAMTSL1, VEGFC), oxidative stress (SOD2), cardiac hypertrophy (MYH7B) and calcium signaling (CAMK2D). Using a transforming growth factor ß1-mediated cardiac fibroblast activation assay, we found that 9 of the 11 loci consisted of genes that exhibited temporal changes in expression or open chromatin conformation supporting their biological relevance to myofibroblast cell state acquisition. By harnessing machine learning to perform large-scale quantification of myocardial interstitial fibrosis using cardiac imaging, we validate associations between cardiac fibrosis and disease, and identify new biologically relevant pathways underlying fibrosis.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Estudio de Asociación del Genoma Completo / Cardiomiopatías Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Nat Genet Asunto de la revista: GENETICA MEDICA Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Estudio de Asociación del Genoma Completo / Cardiomiopatías Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Nat Genet Asunto de la revista: GENETICA MEDICA Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos