Abstract 8: Polygenic Resistance to Blood Pressure Treatment and Stroke Risk

Abstract

Background: Common genetic variation explains up to 40% of blood pressure variation. Despite this compelling physiological impact, the role of common genetic variation in blood pressure treatment and their sequelae remains understudied. We hypothesize that a higher polygenic predisposition to hypertension leads to a poorer response to blood pressure (BP) treatment and higher stroke risk in a primary prevention setting. Methods: We conducted a 2-stage genetic association study using data from the All of Us Research Program (discovery stage) and UK Biobank (replication stage). We included participants on any BP medication at enrollment and excluded those with prior stroke. Participants were categorized as having low, intermediate, or high polygenic predisposition to hypertension according to percentiles (<20, 20-80, >80) of a polygenic risk score of 177 independent risk variants. Uncontrolled systolic BP was defined as >140mmHg and incident stroke was ascertained using Electronic Health Record data and ICD 9/10 codes. We used multivariate logistic and Cox Proportional Hazards regressions, as appropriate, to assess the relationship between genetic predisposition to hypertension and both uncontrolled BP and incident stroke. Results: The discovery stage included 110,892 participants (mean age 58, female sex 58%). Compared to low polygenic risk, intermediate and high risk were linked with 14% (OR 1.14, 95%CI 1.10-1.18) and 30% (OR 1.30, 95%CI 1.24-1.36) surge of uncontrolled BP risk (p<0.001). Similarly, compared to low polygenic risk, intermediate and high risk were associated with 8% (HR 1.08, 95%CI 0.97-1.20) and 15% (HR 1.15, 95%CI 1.00-1.30) increments in stroke risk (p=0.04). These results were replicated in 102,252 participants (mean age 61, female sex 47%) enrolled in the UK Biobank (p<0.05 for both analyses). Conclusions: Among participants on antihypertensive medications, increased genetic predisposition to hypertension correlated with higher risk of uncontrolled BP and stroke. As All of Us and direct-to-consumer companies return genomic information to millions of Americans, our findings support further research, including clinical trials, to explore personalized treatments targeting high-risk subjects for intense interventions.