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Genetic susceptibility, elevated blood pressure, and risk of atrial fibrillation: a Mendelian randomization study

Lookup NU author(s): Dr Dexter CanoyORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2021, The Author(s).Background: Whether elevated blood pressure (BP) is a modifiable risk factor for atrial fibrillation (AF) is not established. We tested (1) whether the association between BP and risk of AF is causal, (2) whether it varies according to individual’s genetic susceptibility for AF, and (3) the extent to which specific BP-lowering drugs are expected to reduce this risk. Methods: First, causality of association was assessed through two-sample Mendelian randomization, using data from two independent genome-wide association studies that included a population of one million Europeans in total. Second, the UK Biobank data of 329,237 participants at baseline was used to study the effect of BP on AF according to genetic susceptibility of developing AF. Third, a possible treatment effect with major BP-lowering drug classes on AF risk was predicted through genetic variants in genes encode the therapeutic targets of each drug class. Estimated drug effects were compared with effects on incident coronary heart disease, for which direct trial evidence exists. Results: The two-sample Mendelian randomization analysis indicated that, on average, exposure to a higher systolic BP increased the risk of AF by 19% (odds ratio per each 10-mmHg [OR] 1.19 [1.12 to 1.27]). This association was replicated in the UK biobank using individual participant data. However, in a further genetic risk-stratified analysis, there was evidence for a linear gradient in the relative effects of systolic BP on AF; while there was no conclusive evidence of an effect in those with low genetic risk, a strong effect was observed among those with high genetic susceptibility for AF. The comparison of predicted treatment effects using genetic proxies for three main drug classes (angiotensin-converting enzyme inhibitors, beta-blockers, and calcium channel blockers) suggested similar average effects for the prevention of atrial fibrillation and coronary heart disease. Conclusions: The effect of elevated BP on the risk of AF is likely to be causal, suggesting that BP-lowering treatment may be effective in AF prevention. However, average effects masked clinically important variations, with a more pronounced effect in individuals with high genetic susceptibility risk for AF.

Publication metadata

Author(s): Nazarzadeh M, Pinho-Gomes A-C, Bidel Z, Canoy D, Dehghan A, Smith Byrne K, Bennett DA, Smith GD, Rahimi K

Publication type: Article

Publication status: Published

Journal: Genome Medicine

Year: 2021

Volume: 13

Issue: 1

Online publication date: 04/03/2021

Acceptance date: 09/02/2021

Date deposited: 25/11/2022

ISSN (electronic): 1756-994X

Publisher: BioMed Central Ltd


DOI: 10.1186/s13073-021-00849-3

PubMed id: 33663581


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Funder referenceFunder name
... a grant from the Oxford Martin School, as well as the PEAK Urban program, from the UKRI’s Global Challenge Research Fund Grant Ref: ES/P011055/1.
Nazarzadeh (grant number: FS/19/36/34346), Pinho-Gomes (grant number: FS/19/64/34673), and Rahimi (grant number: PG/18/65/33872) are supported by the British Heart Foundation.
Rahimi and Canoy are supported by the National Institute of Health Research (NIHR) Oxford Biomedical Research Centre,...