| Title: | Development and External Validation of the DRABackground: HeterozygouGON Risk Score: A Novel 10-Year Cardiovascular Risk Prediction Model for Patients with Heterozygous Familial Hypercholesterolemia |
| Lead Institution: | Cardiff University |
| Principal investigator: |
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Research Questions: 1. Does the DRAGON cardiovascular risk score maintain predictive performance when externally validated in UK Biobank's genetically confirmed familial hypercholesterolemia (FH) patients? 2. What metabolic pathways drive ApoB/LDL discordance in FH patients, and can these identify novel therapeutic targets? Objectives: Primary: Externally validate the DRAGON score in 1,200 UK Biobank FH patients identified through whole-exome sequencing. Secondary: Conduct two-phase metabolomics study investigating ApoB/LDL discordance mechanisms using NMR metabolomics data and targeted mass spectrometry validation. Scientific Rationale: The DRAGON score achieved exceptional performance (C-index 0.823) in Welsh FH patients, identifying remarkable risk heterogeneity. However, external validation across diverse populations is essential before clinical implementation. The score's key component-ApoB/LDL discordance-reflects small, dense LDL predominance but underlying molecular mechanisms remain unknown. Our innovative metabolomics approach will uncover biological pathways driving this discordance, potentially revealing new drug targets. This research addresses critical gaps: validating a promising clinical tool while advancing mechanistic understanding of cardiovascular risk in genetic hypercholesterolemia. The integration of large-scale validation with hypothesis-free metabolomic discovery represents a novel approach to precision medicine in inherited lipid disorders.1 Publication
| Pub ID | Title | Author(s) | Year | Journal |
|---|---|---|---|---|
| 20683 | TUDOR, an ascertainment-aware model for LDLR genetic-testing triage in specialist lipid clinics: development, validation, and UK Biobank transport | Nader Genedy (+5) | 2026 | Journal of Clinical Lipidology |
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