Abstract Details

Title Polygenic Resistance to Blood Pressure Treatment and Stroke Risk

Topic Cerebrovascular Disease and Interventional Neurology

Presentation(s) S6 - Stroke Pathophysiology and Prediction (3:30 PM-3:42 PM)

Poster/Presentation
Number 001

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.

Objective

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

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.

Authors/Disclosures
Shufan Huo, MD, PhD (Yale University) PRESENTER	Dr. Huo has nothing to disclose.
Cyprien Rivier, MD (Yale University)	Dr. Rivier has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pyxis Partners.
Santiago Clocchiatti-Tuozzo (Yale University, Department of Neurology)	Mr. Clocchiatti-Tuozzo has nothing to disclose.
Daniela B. Renedo, MD (Yale University)	Dr. Renedo has nothing to disclose.
Hongyu Zhao (Yale University)	No disclosure on file
Adam De Havenon, MD, FAAN (Yale University)	Dr. De Havenon has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novo Nordisk. Dr. De Havenon has stock in Certus. Dr. De Havenon has stock in TitinKM. The institution of Dr. De Havenon has received research support from NIH/NINDS. Dr. De Havenon has received publishing royalties from a publication relating to health care.
Kevin N. Sheth, MD, FAAN (Yale UniversityDivision of Neuro and Critical Care)	Dr. Sheth has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ceribell. Dr. Sheth has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Zoll. Dr. Sheth has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for NControl. Dr. Sheth has received stock or an ownership interest from Astrocyte. Dr. Sheth has received stock or an ownership interest from Alva. The institution of Dr. Sheth has received research support from Biogen. The institution of Dr. Sheth has received research support from Novartis. The institution of Dr. Sheth has received research support from Bard. The institution of Dr. Sheth has received research support from Hyperfine. Dr. Sheth has received intellectual property interests from a discovery or technology relating to health care.
Guido J. Falcone, MD (Yale School of Medicine)	The institution of Dr. Falcone has received research support from NIH. The institution of Dr. Falcone has received research support from AHA.