Interleukin-6 Receptor Signaling and Abdominal Aortic Aneurysm Growth Rates
Year: 2019
Type: article
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.
Authors: 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. Bailey, Stefan Rose-John, John Danesh, Daniel F. Freitag, Dirk S. Paul, Ziad Mallat
Institutions: Australian National University, University of Cambridge, British Heart Foundation, Inserm, Université Côte d'Azur, Centre Hospitalier Universitaire de Nice, Centre Méditerranéen de Médecine Moléculaire, University of Leicester, Addenbrooke's Hospital, National Institute for Health and Care Research, NIHR Leicester Cardiovascular Biomedical Research Unit, NIHR Leicester Biomedical Research Centre, Odense University Hospital, Centre for Individualised Medicine in Arterial Diseases, Belfast Health and Social Care Trust, Mayo Clinic, Imperial College London, The University of Western Australia, Leeds General Infirmary, University of Leeds, Christian-Albrechts-Universität zu Kiel, Wellcome Sanger Institute, Paris Cardiovascular Research Center
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,277
Awards: NIHR Senior Investigator Award, The United Kingdom Aneurysm Growth Study, Large-scale integrative genomic studies of high-dimensional traits in cardiovascular diseases (renewal), G4211044638, G6195336793, G6874897261, Defining the role(s) of selective subsets of antigen presenting cells in promoting or preventing atherosclerosis. (Renewal), G7475120045, Large-scale integrative studies of risk factors in coronary heart disease: from discovery to application (renewal). (Joint funding with MRC), Vascular smooth muscle cell Orai1 in abdominal aortic aneurysm
OpenAlex ID: W2952979335