Fine-mapping of retinal vascular complexity loci identifies Notch regulation as a shared mechanism with myocardial infarction outcomes.

Autor: Villaplana-Velasco A; The Roslin Institute, Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Edinburgh, Scotland, UK.; Centre for Medical Informatics, Usher Institute, The University of Edinburgh, Edinburgh, Scotland, UK., Pigeyre M; Population Health Research Institute (PHRI), Department of Medicine, Faculty of Health Sciences, McMaster University, McMaster University, Hamilton, Ontario, Canada., Engelmann J; Centre for Medical Informatics, Usher Institute, The University of Edinburgh, Edinburgh, Scotland, UK., Rawlik K; The Roslin Institute, Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Edinburgh, Scotland, UK., Canela-Xandri O; MRC Human Genetics Unit, IGC, The University of Edinburgh, Edinburgh, Scotland, UK., Tochel C; Centre for Medical Informatics, Usher Institute, The University of Edinburgh, Edinburgh, Scotland, UK., Lona-Durazo F; University of Toronto at Mississauga, Mississauga, Ontario, Canada., Mookiah MRK; VAMPIRE project, Computing, School of Science and Engineering, University of Dundee, Dundee, Scotland, UK., Doney A; VAMPIRE project, Computing, School of Science and Engineering, University of Dundee, Dundee, Scotland, UK., Parra EJ; University of Toronto at Mississauga, Mississauga, Ontario, Canada., Trucco E; VAMPIRE project, Computing, School of Science and Engineering, University of Dundee, Dundee, Scotland, UK., MacGillivray T; VAMPIRE project, Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, Scotland, UK., Rannikmae K; Centre for Medical Informatics, Usher Institute, The University of Edinburgh, Edinburgh, Scotland, UK., Tenesa A; The Roslin Institute, Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Edinburgh, Scotland, UK.; Centre for Medical Informatics, Usher Institute, The University of Edinburgh, Edinburgh, Scotland, UK.; MRC Human Genetics Unit, IGC, The University of Edinburgh, Edinburgh, Scotland, UK., Pairo-Castineira E; The Roslin Institute, Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Edinburgh, Scotland, UK., Bernabeu MO; Centre for Medical Informatics, Usher Institute, The University of Edinburgh, Edinburgh, Scotland, UK. Miguel.Bernabeu@ed.ac.uk.; The Bayes Centre, The University of Edinburgh, Edinburgh, Scotland, UK. Miguel.Bernabeu@ed.ac.uk.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2023 May 15; Vol. 6 (1), pp. 523. Date of Electronic Publication: 2023 May 15.
DOI: 10.1038/s42003-023-04836-9
Abstrakt: There is increasing evidence that the complexity of the retinal vasculature measured as fractal dimension, D f , might offer earlier insights into the progression of coronary artery disease (CAD) before traditional biomarkers can be detected. This association could be partly explained by a common genetic basis; however, the genetic component of D f is poorly understood. We present a genome-wide association study (GWAS) of 38,000 individuals with white British ancestry from the UK Biobank aimed to comprehensively study the genetic component of D f and analyse its relationship with CAD. We replicated 5 D f loci and found 4 additional loci with suggestive significance (P < 1e-05) to contribute to D f variation, which previously were reported in retinal tortuosity and complexity, hypertension, and CAD studies. Significant negative genetic correlation estimates support the inverse relationship between D f and CAD, and between D f and myocardial infarction (MI), one of CAD's fatal outcomes. Fine-mapping of D f loci revealed Notch signalling regulatory variants supporting a shared mechanism with MI outcomes. We developed a predictive model for MI incident cases, recorded over a 10-year period following clinical and ophthalmic evaluation, combining clinical information, D f , and a CAD polygenic risk score. Internal cross-validation demonstrated a considerable improvement in the area under the curve (AUC) of our predictive model (AUC = 0.770 ± 0.001) when comparing with an established risk model, SCORE, (AUC = 0.741 ± 0.002) and extensions thereof leveraging the PRS (AUC = 0.728 ± 0.001). This evidences that D f provides risk information beyond demographic, lifestyle, and genetic risk factors. Our findings shed new light on the genetic basis of D f , unveiling a common control with MI, and highlighting the benefits of its application in individualised MI risk prediction.
(© 2023. The Author(s).)
Databáze: MEDLINE
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