Paige, E, Clément, M, Lareyre, F et al. (22 more authors) (2019) Interleukin-6 Receptor Signalling and Abdominal Aortic Aneurysm Growth Rates. Circulation Genomics & Prescision Medicine, 12 (2). e002413. ISSN 2574-8300
Abstract
Background: The Asp358Ala variant (rs2228145; A>C) in the interleukin-6 receptor (IL6R) gene has been implicated in the development of abdominal aortic aneurysms (AAAs), but its effect on AAA growth over time is not known. We aimed to investigate the clinical association between the IL6R-Asp358Ala variant and AAA growth, and to assess the effect of blocking the IL-6 signalling pathway in mouse models of aortic aneurysm rupture or dissection.
Methods: Using data from 2,863 participants with AAA from nine prospective cohorts, age- and sex-adjusted mixed-effects linear regression models were used to estimate the association between the IL6R-Asp358Ala variant and annual change in AAA diameter (mm/year). In a series of complementary randomised trials in mice, the effect of blocking the IL-6 signalling pathways was assessed on plasma biomarkers, systolic blood pressure, aneurysm diameter and time to aortic rupture and death.
Results: After adjusting for age and sex, baseline aneurysm size was 0.55mm (95% confidence interval [CI]: 0.13, 0.98mm) smaller per copy of the minor allele [C] of the Asp358Ala variant. Change in AAA growth was -0.06mm per year [-0.18, 0.06] per copy of the minor allele; a result that was not statistically significant. Although all available worldwide data were used, the genetic analyses were not powered for an effect size as small as that observed. In two mouse models of AAA, selective blockage of the IL-6 trans-signalling pathway, but not combined blockage of both, the classical and trans-signalling pathways, was associated with improved survival (p<0.05).
Conclusions: Our proof-of-principle data are compatible with the concept that IL-6 trans-signalling is relevant to AAA growth, encouraging larger-scale evaluation of this hypothesis.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2018 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/) |
Keywords: | interleukin-6 receptor; abdominal aortic aneurysm; inflammation; genetics |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM) > Discovery & Translational Science Dept (Leeds) |
Funding Information: | Funder Grant number British Heart Foundation FS/18/12/33270 |
Depositing User: | Symplectic Publications |
Date Deposited: | 25 Jan 2019 15:54 |
Last Modified: | 25 Jun 2023 21:41 |
Status: | Published |
Publisher: | American Heart Association |
Identification Number: | 10.1161/CIRCGEN.118.002413 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:141590 |