We will investigate how inflammatory and metabolic pathways jointly shape the development of multimorbidity across dermatological, cardiometabolic, vascular and musculoskeletal conditions. Using UK Biobank, our programme will address:
(i) vascular outcomes, focusing on abdominal/thoracic aortic aneurysm and aortic dissection;
(ii) inflammatory skin diseases (e.g., psoriasis, eczema/atopic dermatitis) as systemic phenotypes linked to metabolic risk;
(iii) common metabolic disorders (type 2 diabetes, obesity, dyslipidaemia, hypertension); and
(iv) major orthopaedic conditions (e.g., osteoarthritis and fragility fracture).
We will integrate hospital and death registries with primary-care diagnoses and prescribing, and leverage imputed genotypes to construct polygenic risk scores (PRS) and pathway scores relevant to inflammation, lipid/glucose regulation and extracellular-matrix biology. Time-to-event and longitudinal models will quantify associations and test interactions between genetic susceptibility, blood-pressure traits (including variability), adiposity, lifestyle, and medications (antihypertensives, lipid-lowering therapy, antidiabetics including incretin-based agents). Where available, imaging-derived aortic measures will be analysed as intermediate phenotypes for mediation and effect-modification analyses. Sensitivity analyses will include exposure lags, active-comparator/new-user designs for drug effects, multiple imputation and quantitative bias analyses. All analyses will be undertaken on the UK Biobank Research Analysis Platform; no individual-level data will be downloaded. This integrated approach aims to identify shared mechanisms and produce actionable risk stratification to support earlier detection, targeted surveillance (e.g., aneurysm), and personalised prevention/therapy across co-existing diseases.
