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Genetic aetiology of blood pressure relates to aortic stiffness with bi-directional causality: evidence from heritability, blood pressure polymorphisms, and Mendelian randomization
Abstract
Aims: Haemodynamic determinants of blood pressure (BP) include cardiac output (CO), systemic vascular resistance (SVR), and arterial stiffness. We investigated the heritability of these phenotypes, their association with BP-related single-nucleotide polymorphisms (SNPs), and the causal association between BP and arterial stiffness. Methods and results: We assessed BP, central BP components, and haemodynamic properties (during a single visit) including CO, SVR, and pulse wave velocity (PWV, measure of arterial stiffness) in 3531 (1934 monozygotic, 1586 dizygotic) female TwinsUK participants. Heritability was estimated using structural equation modelling. Association with 984 BP-associated SNP was examined using least absolute shrinkage and selection operator (LASSO) and generalized estimating equation regression. One and two-sample Mendelian randomization (MR) was used to estimate the causal direction between BP and arterial stiffness including data on 436 419 UK Biobank participants. We found high heritability for systolic and pulsatile components of BP (>50%) and PWV (65%) with overlapping genes accounting for >50% of their observed correlation. Environmental factors explained most of the variability of CO and SVR (>80%). Regression identified SNPs (n = 5) known to be associated with BP to also be associated with PWV. One-sample MR showed evidence of bi-directional causal association between BP and PWV in TwinsUK participants. Two-sample MR, confirmed a bi-directional causal effect of PWV on BP (inverse variance weighted (IVW) beta = 0.11, P < 0.02) and BP on arterial stiffness (IVW beta = 0.004, P < 0.0001). Conclusion: The genetic basis of BP is mediated not only by genes regulating BP but also by genes that influence arterial stiffness. Mendelian randomization indicates a bi-directional causal association between BP and arterial stiffness.
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Despite numerous GWAS of peripheral blood pressure, few studies have focused on genetic associations with central blood pressure.
“Despite numerous GWAS of peripheral BP, few studies have focused on genetic associations with central BP [29,30].”
From Genetic variation in CCDC93 is associated with elevated central systolic blood pressure, impaired arterial relaxation, and mitochondrial dysfunction (2024) · cites this paper as [30]
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Self-citationUsing multiple genetic variants as instrumental variables for modifiable risk factors
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“Although PWV is a haemodynamic determinant of the pulsatile components of BP, it is influenced by BP via the non-linear elastic properties of wall of the artery which result in a functional stiffening of the artery when distended by a higher BP. Long-term effect of steady state or pulsatile BP components may also lead…”
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Kumar, N., Yang, M.-L., Sun, P., Hunker, K. L., Li, J., Jia, J., Fan, F., Wang, J., Ning, X., Gao, W., et al. (2024) · PLOS Genetics · doi:10.1371/journal.pgen.1011151 · Cited by 1
Metadata
- Authors
- Cecelja, M., Keehn, L., Ye, L., Spector, T. D., Hughes, A. D., & Chowienczyk, P.
- Affiliations
- Cardiovascular Division, Department of Clinical Pharmacology, King’s College London British Heart Foundation Centre, St Thomas’ Hospital , Westminster Bridge Road, London SE1 7EH, UK
- Department of Twin Research and Genetic Epidemiology, King’s College London, St Thomas’ Hospital , Westminster Bridge Road, London SE1 7EH, UK
- Department of Population Science and Experimental Medicine, Institute of Cardiovascular Sciences, University College London , 69 Chenies Mews, London W1T 7HA, UK
- Venue
- European Heart Journal
- Publisher
- Oxford University Press (OUP)
- Published
- 2020-05-01
- Volume
- 41
- Issue
- 35
- Pages
- 3314-3322
- ISSN
- 0195-668X
- 1522-9645
- Cited by
- 48
- References
- 7
- Language
- en
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Funders
- British Heart Foundation Centre for Research Excellence Career Development Fellowship
- British Heart Foundation Special Project (SP/12/4/29573)
- Wellcome Trust
- European Community’s Seventh Framework Programme (FP7/2007–13)
- National Institute for Health Research BioResource
- Clinical Research Facility and Biomedical Research Centre
- NHS Foundation Trust and King’s College London
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