Interleukin-6 Receptor Signaling and Abdominal Aortic Aneurysm Growth Rates

Ellie Paige, Marc Clément, Fabien Lareyre, Michael Sweeting, Juliette Raffort, Céline Grenier, Alison Finigan, James Harrison, James E. Peters, Benjamin B. Sun, Adam S. Butterworth, Seamus C. Harrison, Matthew J. Bown, Jes S. Lindholt, Stephen A. Badger, Iftikhar J. Kullo, Janet Powell, Paul E. Norman, D. Julian A. Scott, Marc A. BaileyStefan Rose-John, John Danesh, Daniel F. Freitag, Dirk S. Paul, Ziad Mallat*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

Background: The Asp358Ala variant (rs2228145; A>C) in the IL (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 signaling pathway in mouse models of aortic aneurysm rupture or dissection. Methods: Using data from 2863 participants with AAA from 9 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/y). In a series of complementary randomized trials in mice, the effect of blocking the IL-6 signaling 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 0.55 mm (95% CI, 0.13-0.98 mm) smaller per copy of the minor allele [C] of the Asp358Ala variant. Change in AAA growth was -0.06 mm per year (-0.18 to 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 2 mouse models of AAA, selective blockage of the IL-6 trans-signaling pathway, but not combined blockage of both, the classical and trans-signaling pathways, was associated with improved survival (P<0.05). Conclusions: Our proof-of-principle data are compatible with the concept that IL-6 trans-signaling is relevant to AAA growth, encouraging larger-scale evaluation of this hypothesis.

Original languageEnglish
Article numbere002413
Pages (from-to)84-93
Number of pages10
JournalCirculation: Genomic and Precision Medicine
Volume12
Issue number2
DOIs
Publication statusPublished - 1 Feb 2019
Externally publishedYes

Bibliographical note

Funding Information:
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).

Publisher Copyright:
© 2019 American Heart Association, Inc.

Keywords

  • alleles
  • aortic aneurysm
  • genetics
  • inflammation
  • interleukins

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