Paper

Interleukin-6 Receptor Signalling and Abdominal Aortic Aneurysm Growth Rates

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

2018

Overview

Objective: 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 aneurysm rupture. Approach: 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. There was no evidence of a reduction in AAA growth rate (change in growth=-0.06mm per year [-0.18, 0.06] per copy of the minor allele). 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. Footnotes * Additional information on the experimental mouse models and results from genetic epidemiological analysis after further adjustment for current smoking, diabetes status, body mass index and method used to measure aneurysm size.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Alleles / Aneurysms / Animal models / Aortic aneurysms / Blood pressure / Body mass index / Clinical trials / Cytokines / Diabetes mellitus / Epidemiology / Genetic analysis / Genetics / Growth rate / Interleukin 6 / Interleukin 6 receptors / Regression analysis / Rupture / Signal transduction / Smoking