Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening cardiovascular condition with high mortality and no proven medical therapy. This project will use UK Biobank Tier 1 data, including genetic, clinical, and medication information, to investigate the role of aldosterone pathway activation in TAAD risk. TAAD cases will be identified using ICD-10 codes (I71.0-I71.2), and covariates will include age, sex, ethnicity, BMI, blood pressure, lipids, diabetes, smoking, alcohol, and use of other antihypertensive medications.
We will perform observational analyses of mineralocorticoid receptor antagonist (MRA) use using Cox proportional hazards models to estimate hazard ratios for incident TAAD, adjusting for demographic, lifestyle, and clinical factors. Sensitivity analyses will assess effect heterogeneity by sex, age, hypertension status, and MRA subtype. To strengthen causal inference, Mendelian randomisation (MR) will be conducted using genetic instruments associated with aldosterone pathway activity, including cis-variants in NR3C2 and CYP11B2. The primary MR analysis will use inverse-variance weighted estimates, with MR-Egger, weighted median/mode, and MR-PRESSO as sensitivity tests.
Approximately 2,000-2,500 incident TAAD cases are expected, providing >80% power to detect moderate effect sizes. Findings will clarify the causal role of aldosterone signaling in TAAD and assess the potential for repurposing widely available drugs to prevent aortic rupture. All results will be shared via open-access publications, with reproducible code to maximize scientific transparency and public health benefit.