Genetics of myocardial interstitial fibrosis in the human heart and association with disease.
Victor NauffalPaolo Di AchilleMarcus D R KlarqvistJonathan W CunninghamMatthew C HillJames Paul PirruccelloLu-Chen WangValerie N MorrillSeung Hoan ChoiShaan KhurshidSamuel Freesun FriedmanMahan NekouiCarolina RoselliKenney NgAnthony A PhilippakisPuneet BatraPatrick T EllinorSteven A LubitzPublished in: Nature genetics (2023)
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.
Keyphrases
- left ventricular
- heart failure
- aortic stenosis
- transforming growth factor
- machine learning
- magnetic resonance imaging
- atrial fibrillation
- genome wide
- hypertrophic cardiomyopathy
- genome wide association
- cardiovascular disease
- oxidative stress
- rheumatoid arthritis
- endothelial cells
- left atrial
- aortic valve replacement
- transcatheter aortic valve implantation
- epithelial mesenchymal transition
- mitral valve
- type diabetes
- liver fibrosis
- artificial intelligence
- high throughput
- emergency department
- stem cells
- dna damage
- skeletal muscle
- molecular dynamics simulations
- ejection fraction
- idiopathic pulmonary fibrosis
- signaling pathway
- adipose tissue
- diabetic rats
- induced apoptosis
- ischemia reperfusion injury
- dna methylation
- mass spectrometry
- acute heart failure
- cardiovascular events
- blood glucose
- bone marrow