Cumulative and measured blood pressure, polygenic susceptibility, and cardiovascular disease risk

Background Single blood pressure (BP) measurements do not fully reflect the cumulative vascular burden of sustained hypertension. The contribution of genetic susceptibility and cumulative BP exposure to cardiovascular risk beyond a single measurement remains incompletely defined. Purpose To examine the influence of BP polygenic scores on midlife trajectories, evaluate associations of cumulative and baseline BP and genetic susceptibility with incident cardiovascular disease (CVD), and assess incremental predictive value in the UK Biobank (UKB). Methods Linear mixed-effects models were used to estimate sex-specific BP trajectories from ≥3 linked primary care measurements between ages 40 and 60, with cumulative burden quantified as area under the curve (AUC). Genome-wide BP polygenic scores (PGS) were used to evaluate genetic effects on midlife BP trajectories. Associations of baseline BP, cumulative BP burden, and BP PGS with incident myocardial infarction, ischaemic stroke, heart failure, and composite CVD were estimated using Cox models with follow-up from age 60 (landmark analysis), stratified by antihypertensive use. Incremental predictive performance was evaluated using likelihood ratio tests, C-statistics, and integrated discrimination improvement. Results Among 92,729 European-ancestry participants, each SD increase in SBP PGS was associated with 6.4 mmHg higher mean SBP at age 58, with effects increasing with age (PGS×age p≤0.005). Among untreated participants, per 10 mmHg higher time-averaged SBP (ages 40–60) was associated with a higher hazard of composite CVD than similarly scaled baseline SBP (HR 1.19 [95% CI 1.15–1.23] vs 1.08 [1.06–1.09]), with the largest differences observed for heart failure and ischaemic stroke. In per SD analyses, after mutual adjustment for baseline SBP and SBP PGS, cumulative BP burden remained independently associated with heart failure (HR 1.18 [1.08–1.29]), ischaemic stroke (HR 1.12 [1.00–1.25]), and composite CVD (HR 1.10 [1.04–1.16]). SBP PGS associations were modestly attenuated after adjustment for cumulative BP burden (HR 1.09 to 1.07) but remained statistically significant. C-statistics were similar across models (0.67–0.70), whereas IDI demonstrated modest incremental gains when adding AUC to baseline SBP models and PGS to models including measured BP. Findings were consistent for diastolic BP. Conclusions Cumulative midlife BP burden provides prognostic information beyond single measurements, particularly for heart failure. Polygenic BP susceptibility captures cardiovascular risk not fully reflected in measured BP. Integration of longitudinal BP assessment and genetic susceptibility may enhance cardiovascular risk stratification.Genetic PRS, Cumulative BP & CVD EventsBP AUC & Composite CVD Events