Polygenic Susceptibility to Hypertension and Blood Pressure Control in Stroke Survivors
Abstract
Background and Objectives
Blood pressure (BP) is often not at goal in stroke survivors, leaving individuals vulnerable to additional vascular events. Given that BP is a highly heritable trait, we hypothesize that a higher polygenic susceptibility to hypertension (PSH) leads to worse BP control in stroke survivors.
Methods
We conducted a study within the UK Biobank evaluating persons of European ancestry who survived an ischemic or hemorrhagic stroke. To model the PSH, we created polygenic risk scores (PRSs) for systolic and diastolic BP using 732 genetic variants. We divided the PRSs into quintiles and used linear/logistic regression to test whether higher PSH led to higher observed BP, uncontrolled BP (systolic BP > 140 mm Hg or diastolic BP > 90 mm Hg), and resistant BP (uncontrolled BP despite being on ≥3 antihypertensive drugs). We conducted an independent replication using data from the Vitamin Intervention for Stroke Prevention (VISP) trial.
Results
We analyzed 5,940 stroke survivors. When comparing stroke survivors with very low vs very high PSH, the mean systolic BP was 137 (SD 18) vs 143 (SD 20, p < 0.001), the mean diastolic BP was 81 (SD 10) vs 84 (SD 11, p < 0.001), the prevalence of uncontrolled BP was 42.8% vs 57.2% (p < 0.001), and the prevalence of resistant hypertension was 3.9% vs 11% (p < 0.001). Results remained significant using multivariable models (p < 0.001) and were replicated in the VISP study (all tests with p < 0.05).
Discussion
A higher PSH is associated with worse BP control in stroke survivors. These findings point to genetic predisposition as an important determinant of poorly controlled BP in this population.
Get full access to this article
View all available purchase options and get full access to this article.
References
1.
GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol. 2021;20(10):795-820. doi.
2.
Flach C, Muruet W, Wolfe CDA, Bhalla A, Douiri A. Risk and secondary prevention of stroke recurrence: a population-base cohort study. Stroke. 2020;51(8):2435-2444. doi.
3.
Pendlebury ST, Rothwell PM. Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: a systematic review and meta-analysis. Lancet Neurol. 2009;8(11):1006-1018. doi.
4.
Corraini P, Henderson VW, Ording AG, Pedersen L, Horváth-Puhó E, Sørensen HT. Long-term risk of dementia among survivors of ischemic or hemorrhagic stroke. Stroke. 2017;48(1):180-186. doi.
5.
Sennfält S, Norrving B, Petersson J, Ullberg T. Long-term survival and function after stroke. Stroke. 2019;50(1):53-61. doi.
6.
Dhamoon MS, Longstreth WT, Bartz TM, Kaplan RC, Elkind MSV. Disability trajectories before and after stroke and myocardial infarction: the cardiovascular health study. JAMA Neurol. 2017;74(12):1439-1445. doi.
7.
Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 guideline for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline from the American Heart Association/American Stroke Association. Stroke. 2021;52(7):e364-e467. doi.
8.
Zonneveld TP, Richard E, Vergouwen MD, et al. Blood pressure-lowering treatment for preventing recurrent stroke, major vascular events, and dementia in patients with a history of stroke or transient ischaemic attack. Cochrane Database Syst Rev. 2018;7:CD007858. doi.
9.
Santos D, Dhamoon MS. Trends in antihypertensive medication use among individuals with a history of stroke and hypertension, 2005 to 2016. JAMA Neurol. 2020;77(11):1382-1389.
10.
Evangelou E, Warren HR, Mosen-Ansorena D, et al. Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. Nat Genet. 2018;50(10):1412-1425. doi.
11.
Choi SW, Mak TS-H, O'Reilly PF. Tutorial: a guide to performing polygenic risk score analyses. Nat Protoc. 2020;15(9):2759-2772. doi.
12.
Vaura F, Kauko A, Suvila K, et al. Polygenic risk scores predict hypertension onset and cardiovascular risk. Hypertension. 19792021;77(4):1119-1127. doi.
13.
Ou Y-N, Yang Y-X, Shen X-N, et al. Genetically determined blood pressure, antihypertensive medications, and risk of Alzheimer's disease: a Mendelian randomization study. Alzheimers Res Ther. 2021;13(1):41. doi.
14.
Bycroft C, Freeman C, Petkova D, et al. The UK Biobank resource with deep phenotyping and genomic data. Nature. 2018;562(7726):203-209. doi.
15.
Woodfield R, Grant I, Sudlow CLM. Accuracy of electronic health record data for identifying stroke cases in large-scale epidemiological studies: a systematic review from the UK biobank stroke outcomes group. PLoS One. 2015;10:e0140533. doi.
16.
Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D. Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006;38(8):904-909. doi.
17.
Howie BN, Donnelly P, Marchini J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 2009;5(6):e1000529. doi.
18.
McCarthy S, Das S, Kretzschmar W, et al. A reference panel of 64,976 haplotypes for genotype imputation. Nat Genet. 2016;48(10):1279-1283. doi.
19.
Huang J, Howie B, McCarthy S, et al. Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel. Nat Commun. 2015;6:8111. doi.
20.
1000 Genomes Project Consortium, Auton A, Brooks LD, Durbin RM, et al. A global reference for human genetic variation. Nature. 2015;526(7571):68-74. doi.
21.
Chou W-C, Zheng H-F, Cheng C-H, et al. A combined reference panel from the 1000 genomes and UK10K projects improved rare variant imputation in European and Chinese samples. Sci Rep. 2016;6(1):39313. doi.
22.
Blood-pressure measurement procedures using ACE [online]. Accessed September 23, 2021. biobank.ctsu.ox.ac.uk/crystal/refer.cgi?id=100225.
23.
Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task F. Hypertension. 2018;71(6):1269-1324. doi.
24.
Wain LV, Vaez A, Jansen R, et al. Novel blood pressure locus and gene discovery using genome-wide association study and expression data sets from blood and the kidney. Hypertension. 2017;70(3):e4-e19. doi.
25.
Purcell S, Neale B, Todd-Brown K, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81(3):559-575. doi.
26.
Choi SW, O'Reilly PF. PRSice-2: polygenic Risk Score software for biobank-scale data. GigaScience. 2019;8(7):giz082. doi.
27.
R Core Team. R: A Language and Environment for Statistical Computing [online]. R Foundation for Statistical Computing; 2020. R-project.org/.
28.
Spence JD, Howard VJ, Chambless LE, et al. Vitamin intervention for stroke prevention (VISP) trial: rationale and design. Neuroepidemiology. 2001;20(1):16-25. doi.
29.
Toole JF, Malinow MR, Chambless LE, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA. 2004;291(5):565-575. doi.
30.
Williams SR, Hsu F-C, Keene KL, et al. Shared genetic susceptibility of vascular-related biomarkers with ischemic and recurrent stroke. Neurology. 2016;86(4):351-359. doi.
31.
Prosser J, MacGregor L, Lees KR, Diener HC, Hacke W, Davis S. Predictors of early cardiac morbidity and mortality after ischemic stroke. Stroke. 2007;38(8):2295-2302. doi.
32.
Mohan KM, Wolfe CDA, Rudd AG, Heuschmann PU, Kolominsky-Rabas PL, Grieve AP. Risk and cumulative risk of stroke recurrence: a systematic review and meta-analysis. Stroke. 2011;42(5):1489-1494. doi.
33.
Hackam DG, Spence JD. Combining multiple approaches for the secondary prevention of vascular events after stroke: a quantitative modeling study. Stroke. 2007;38(6):1881-1885. doi.
34.
Fuchs FD, Whelton PK. High blood pressure and cardiovascular disease. Hypertension. 2020;75(2):285-292. doi.
35.
Sierra C. Hypertension and the risk of dementia. Front Cardiovasc Med. 2020;7:5. doi.
36.
Pazoki R, Dehghan A, Evangelou E, et al. Genetic predisposition to high blood pressure and lifestyle factors: associations with midlife blood pressure levels and cardiovascular events. Circulation. 2018;137(7):653-661. doi.
37.
Abraham G, Malik R, Yonova-Doing E, et al. Genomic risk score offers predictive performance comparable to clinical risk factors for ischaemic stroke. Nat Commun. 2019;10(1):5819. doi.
38.
Falcone GJ, Biffi A, Devan WJ, et al. Burden of risk alleles for hypertension increases risk of intracerebral hemorrhage. Stroke. 2012;43(11):2877-2883. doi.
39.
Padmanabhan S, Dominiczak AF. Genomics of hypertension: the road to precision medicine. Nat Rev Cardiol. 2021;18(4):235-250. doi.
40.
Jiang X, Holmes C, McVean G. The impact of age on genetic risk for common diseases. PLoS Genet. 2021;17(8):e1009723. doi.
41.
Marston NA, Kamanu FK, Nordio F, et al. Predicting benefit from evolocumab therapy in patients with atherosclerotic disease using a genetic risk score: results from the FOURIER trial. Circulation. 2020;141(8):616-623. doi.
42.
Damask A, Steg PG, Schwartz GG, et al. Patients with high genome-wide polygenic risk scores for coronary artery disease may receive greater clinical benefit from Alirocumab treatment in the ODYSSEY OUTCOMES trial. Circulation. 2020;141(8):624-636. doi.
43.
Riveros-Mckay F, Weale ME, Moore R, et al. An integrated polygenic tool substantially enhances coronary artery disease prediction. Circ Genomic Precis Med. 2021;14(2):e003304.
44.
Widén E, Junna N, Ruotsalainen S, et al. How communicating polygenic and clinical risk for atherosclerotic cardiovascular disease impacts health behavior: an observational follow-up study. Circ Genom Precis Med. 2022;15(2):e003459. doi.
Information & Authors
Information
Published In
Copyright
© 2023 American Academy of Neurology.
Publication History
Received: May 8, 2022
Accepted: November 16, 2022
Published online: January 23, 2023
Published in print: April 11, 2023
Disclosure
J.N. Acosta is supported by the American Heart Association Bugher Research Fellowship. C.P. Both, Z.S. Demarais, C.J. Conlon, A.C. Leasure, V.M. Torres-Lopez, A. De Havenon, and N. Petersen have nothing to disclose. T.M. Gill is supported by the NIH (P30AG021342). L.H. Sansing is supported by the NIH (NIH R01NS097728, R01NS095993, and U01NS113445) and AHA (EIA34770133). K.N. Sheth is supported by the NIH (R03NS112859, R01NS110721, R01NS075209, U01NS113445, U01NS106513, R01NR01833, U24NS107215, and U24NS107136) and the AHA (17CSA33550004 and 817874). G.J. Falcone is supported by the NIH (K76AG059992 and R03NS112859) and AHA (18IDDG34280056 and 817874) and the Yale Pepper Center (P30AG021342). Go to Neurology.org/N for full disclosures.
Study Funding
American Heart Association/Bugher Foundation (grant nos. 817874 and 814669) and the NIH (grant no. P30AG021342).
Authors
Metrics & Citations
Metrics
Citations
Download Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Select your manager software from the list below and click Download.
Cited By
- Secondary Prevention in Patients With Stroke Versus Myocardial Infarction: Analysis of 2 National Cohorts, Journal of the American Heart Association, 13, 9, (2024).https://doi.org/10.1161/JAHA.123.033322
- Polygenic Susceptibility to Hypertension and Cognitive Performance in Middle-aged Persons Without Stroke or Dementia, Neurology, 101, 5, (e512-e521), (2023)./doi/10.1212/WNL.0000000000207427
- Polygenic Risk Scores in the Clinic, Neurology, 100, 15, (693-695), (2023)./doi/10.1212/WNL.0000000000206899
- The role of depression and antidepressant treatment in antihypertensive medication adherence and persistence: Utilising electronic health record data, Journal of Psychiatric Research, 168, (269-278), (2023).https://doi.org/10.1016/j.jpsychires.2023.10.018
Loading...
View Options
Get Access
Login options
Check if you have access through your login credentials or your institution to get full access on this article.
Personal login Institutional LoginPurchase Options
The neurology.org payment platform is currently offline. Our technical team is working as quickly as possible to restore service.
If you need immediate support or to place an order, please call or email customer service:
- 1-800-638-3030 for U.S. customers - 8:30 - 7 pm ET (M-F)
- 1-301-223-2300 for customers outside the U.S. - 8:30 - 7 pm ET (M-F)
- [email protected]
We appreciate your patience during this time and apologize for any inconvenience.