Polygenic risk stratifies atrial fibrillation into biologically distinct prognostic phenotypes
E Ghanbari, K Jakobs, A Sannino, M Witkowski, T Reinberger, N Kraenkel, U Rauch, U Landmesser, F Barbieri, M ReinthalerAbstract
Background
Polygenic risk scores (PRS) for atrial fibrillation (AF) predict incident disease, but their relevance after AF diagnosis is unclear. We investigated whether AF PRS delineates distinct biological phenotypes and prognostic trajectories among individuals with established AF.
Methods
We analyzed 27,318 UK Biobank participants with AF. Standardized AF PRS and cardiometabolic trait PRS were obtained from the UK Biobank precomputed PRS resource. AF PRS was evaluated continuously and across quintiles. Associations with cross-trait PRS, comorbidities, and outcomes were assessed using multivariable regression and Cox models adjusted for age, sex, comorbidities, and oral anticoagulant use. In a cardiac magnetic resonance (CMR) subset (n = 1,548), associations between AF PRS and atrial and ventricular structure were tested.
Results
The highest AF PRS quintile (Q5) included 5,255 participants (mean 1.86 ± 0.48), and the lowest quintile (Q1) included 5,254 participants (–0.79 ± 0.42). Across AF PRS quintiles, lower AF genetic susceptibility was accompanied by higher cardiometabolic genetic burden, including hypertension PRS (ΔQ1–Q5 = +0.38; β = 0.0896, 95% CI 0.0811–0.0981), composite cardiovascular disease PRS (Δ = +0.35; β = 0.0826, 95% CI 0.0740–0.0911), coronary artery disease PRS, body mass index PRS, and diabetes PRS (all p < 0.001). Cardiometabolic comorbidities were more prevalent in Q1 versus Q5, including heart failure, hypertension, diabetes, obesity and chronic kidney disease (all p < 0.05). Higher AF PRS was associated with lower all-cause mortality (Q5 vs Q1 HR 0.67, 95% CI 0.62–0.73), cardiovascular death (HR 0.72, 0.65–0.80), and MACE (HR 0.79, 0.74–0.85; all p < 0.001). In CMR, higher AF PRS was linked to biatrial enlargement and reduced atrial function (LAVI β 1.56; LAEF β –1.95) alongside less ventricular remodeling (LVMI β –0.62; LVEDVI β –1.38).
Conclusions
In conclusion, within established AF cases, PRS delineates atrial- from cardiometabolic-predominant trajectories with distinct structural and prognostic profiles, supporting biologically informed risk stratification beyond traditional incident-risk prediction.Figure