Polygenic Resistance to Blood Pressure Treatment and Stroke Risk: Insights from the All of Us Research Program.

Objective: Our goal was to investigate the impact of polygenic susceptibility to hypertension on systolic blood pressure (BP), uncontrolled hypertension, and stroke among hypertensive patients with BP treatment prescription.

Methods: This genetic association study used data from the All of Us Research Program (2017-2023) and replicated findings using the United Kingdom Biobank (2006-2010). Participants prescribed BP medication ≥4 years, with diagnosed hypertension or ≥2 systolic BP measurements >130mmHg, and without a previous stroke were categorized as having low, intermediate, or high polygenic susceptibility to hypertension using percentiles (<20, 20-80, >80) of a polygenic risk score for systolic BP. Primary outcomes were systolic BP, and uncontrolled hypertension (systolic BP > 140mmHg). The secondary outcome was incident stroke during 4-years follow-up. Multivariable linear, logistic, and Cox proportional hazards regressions assessed the influence of polygenic susceptibility to hypertension on each outcome.

Results: A total of 51,006 participants (mean age = 56, 55% female) were included. Intermediate and high genetic risk were associated with higher systolic BP (intermediate: beta = 2.55, standard error [SE] = 0.16, high: beta = 4.81, SE= 0.20, all p < 0.001), and with 36% (odds ratio [OR] = 1.36, 95% confidence interval [CI] = 1.28-1.44) and 80% (OR = 1.80, 95% CI = 1.69-1.93) higher odds of uncontrolled hypertension, respectively. Furthermore, high genetic risk was associated with 23% (hazard ratio [HR] = 1.23, 95% CI = 1.03-1.46) increased stroke hazard. These results were replicated in 84,259 participants (mean age = 61, female sex = 46%).

Interpretation: Among hypertensive adults who were prescribed BP medication, polygenic susceptibility to hypertension correlates with higher systolic BP and higher rates of uncontrolled hypertension and stroke. Our findings support further research on personalized interventions targeting high-risk individuals. ANN NEUROL 2025.