Mapping human genetic associations to drug targets in valvular heart disease: an integrative evidence synthesis

BACKGROUND: Valvular heart disease (VHD) lacks disease-modifying pharmacological therapies. Drug repurposing guided by human genetics may help identify therapeutic opportunities. We aimed to integrate human genetic associations, drug-target information, and clinical evidence to identify repurposing opportunities and prioritise potentially druggable targets across the VHD spectrum. METHODS: We retrieved VHD-associated genetic variants from the NHGRI-EBI Genome-Wide Association Studies Catalogue and Ensembl, interrogated annotated genes in the Open Targets Platform, and evaluated linked drugs through structured searches of MEDLINE and ClinicalTrials.gov. The study protocol was registered in PROSPERO (CRD420251071741). FINDINGS: We identified 1464 genetic associations corresponding to 844 unique variants and 582 candidate genes. Of these genes, 431 had tractability information and 51 had linked compounds, comprising 388 distinct pharmacological agents, 273 in phase 3 or 4 of clinical development. Drug-linked targets were concentrated in aortic stenosis. Clinical evidence supported therapeutic potential for 14 drugs, with preclinical or mechanistic cardiovascular support for eight additional drugs and adverse cardiovascular signals for four. An exploratory evidence-weighted framework prioritised targets according to genetic-functional evidence, tissue and mechanistic context, and translational tractability. INTERPRETATION: This genetics-informed evidence synthesis identifies drug-repurposing opportunities and a substantial gap between genetically supported targets and available therapies. The findings provide a hypothesis-generating framework for mechanistic validation and future valve-focused studies.