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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

Cecelja, M; Keehn, L; Ye, L; Spector, TD; Hughes, AD; Chowienczyk, P; (2020) Genetic aetiology of blood pressure relates to aortic stiffness with bi-directional causality: evidence from heritability, blood pressure polymorphisms, and Mendelian randomization. European Heart Journal , 41 (35) pp. 3314-3322. 10.1093/eurheartj/ehaa238. Green open access

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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.

Type: Article
Title: Genetic aetiology of blood pressure relates to aortic stiffness with bi-directional causality: evidence from heritability, blood pressure polymorphisms, and Mendelian randomization
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/eurheartj/ehaa238
Publisher version: http://dx.doi.org/10.1093/eurheartj/ehaa238
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Arterial stiffness, Blood pressure, Genes, Haemodynamics, Mendelian randomization
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Population Science and Experimental Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/10097262
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