Genetics of myocardial interstitial fibrosis in the human heart and association with disease

Year: 2023

Type: article

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 β1-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.

Source: Nature Genetics

DOI: 10.1038/s41588-023-01371-5

Authors: Victor Nauffal, Paolo Di Achille, Marcus D. R. Klarqvist, Jonathan W. Cunningham, Matthew C. Hill, James P. Pirruccello, Lu-Chen Weng, Valerie N. Morrill, Seung Hoan Choi, Shaan Khurshid, Samuel F. Friedman, Mahan Nekoui, Carolina Roselli, Kenney Ng, Anthony A. Philippakis, Puneet Batra, Patrick T. Ellinor, Steven A. Lubitz

Institutions: Broad Institute, Brigham and Women's Hospital, Massachusetts General Hospital, University of California, San Francisco, University Medical Center Groningen, University of Groningen, IBM Research - Cambridge (United States), Harvard University

Language: English

Topic: Cardiac Fibrosis and Remodeling

Subfield: Cardiology and Cardiovascular Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $11,690

Funders: Foundation for the National Institutes of Health, American Heart Association, Sarnoff Cardiovascular Research Foundation, Fondation Leducq, National Institutes of Health, National Heart, Lung, and Blood Institute

OpenAlex ID: W4366495746