Polygenic Resistance to Blood Pressure Treatment and Stroke Risk
Shufan Huo1, Cyprien Rivier1, Santiago Clocchiatti-Tuozzo2, Daniela Renedo1, Hongyu Zhao1, Adam De Havenon1, Kevin Sheth3, Guido Falcone4
1Yale University, 2Yale University, Department of Neurology, 3Yale University Division of Neuro and Critical Care, 4Yale School of Medicine
Objective:

To investigate the impact of polygenic predisposition to hypertension on blood pressure (BP) treatment response and stroke risk in primary prevention.

Background:

Common genetic variation explains up to 40% of inter-individual BP variability. Despite this compelling physiological impact, its role in BP treatment and its sequelae remains understudied.

Design/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 without prior stroke on any BP medication at enrollment. Subjects were categorized as having low, intermediate, or high polygenic predisposition to hypertension using percentiles (<20, 20-80, >80) of a polygenic risk score of 177 independent risk variants. Resistant hypertension was defined as systolic BP >140mmHg and incident stroke was ascertained using EHR data and ICD 9/10 codes. We used multivariable logistic (adjusted to age, sex, genetic ancestry) and Cox Proportional Hazards regressions (additionally adjusted to cardiovascular risk factors), as appropriate, to assess the relationship between genetic predisposition to hypertension and both resistant hypertension and incident stroke.

Results:

The discovery stage included 110,694 participants (mean age 58, 58% female). Compared to low polygenic risk, intermediate and high risk were associated with 14% (OR 1.14, 95%CI 1.10-1.19) and 30% (OR 1.30, 95%CI 1.24-1.37) increase of resistant hypertension (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) increased stroke hazard (p=0.04). These results were replicated in 102,252 participants (mean age 61, female sex 47%) from the UK Biobank (p<0.05 for both analyses).

Conclusions:

Among participants on antihypertensive medication, increased genetic predisposition to hypertension correlates with higher risk of resistant hypertension and stroke. As direct-to-consumer companies return genomic information to millions of Americans, our findings support further research, including clinical trials, on personalized interventions targeting high-risk subjects.

10.1212/WNL.0000000000206202