CIRCGEN.118.002413.pdf (1.06 MB)
Download file

Interleukin-6 Receptor Signalling and Abdominal Aortic Aneurysm Growth Rates.

Download (1.06 MB)
journal contribution
posted on 22.05.2019, 14:40 by E Paige, M Clément, F Lareyre, M Sweeting, J Raffort, C Grenier, A Finigan, J Harrison, JE Peters, BB Sun, AS Butterworth, SC Harrison, MJ Bown, JS Lindholt, SA Badger, IJ Kullo, J Powell, PE Norman, JA Scott, MA Bailey, S Rose-John, J Danesh, DF Freitag, DS Paul, Z Mallat
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.

Funding

The Cardiovascular Epidemiology Unit is supported by the UK Medical Research Council (MR/L003120/1), British Heart Foundation (RG/13/13/30194), and National Institute for Health Research (Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. Dr Rose-John was supported by grants of the Deutsche Forschungsgemeinschaft (CRC877, project A1) and the German Cluster of Excellence 306 Inflammation at Interfaces. The Leeds Aneurysm Development Study was funded by the Garfield Weston Foundation and Dr Bailey is supported by the British Heart Foundation. Dr Mallat is supported by the British Heart Foundation (RG/79120 and RG/79915).

History

Citation

Circulation: Genomic and Precision Medicine, 2019, 12(2)

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Cardiovascular Sciences

Version

VoR (Version of Record)

Published in

Circulation: Genomic and Precision Medicine

Publisher

American Heart Association, Lippincott, Williams & Wilkins

eissn

2574-8300

Acceptance date

15/01/2019

Copyright date

2019

Available date

22/05/2019

Publisher version

https://www.ahajournals.org/doi/10.1161/CIRCGEN.118.002413

Notes

The Data Supplement is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCGEN.118.002413

Language

en

Usage metrics

Categories

Licence

Exports