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12. Interleukin-6 Receptor Signaling and Abdominal Aortic Aneurysm Growth Rates.

Author

Paige E, Clément M, Lareyre F, Sweeting M, Raffort J, Grenier C, Finigan A, Harrison J, Peters JE, Sun BB, Butterworth AS, Harrison SC, Bown MJ, Lindholt JS, Badger SA, Kullo IJ, Powell J, Norman PE, Scott DJA, Bailey MA, Rose-John S, Danesh J, Freitag DF, Paul DS, and Mallat Z

Subjects
Alleles, Angiotensin II toxicity, Animals, Antibodies immunology, Aortic Aneurysm, Abdominal metabolism, Aortic Aneurysm, Abdominal mortality, Biomarkers metabolism, Disease Models, Animal, Humans, Interleukin-6 blood, Linear Models, Mice, Polymorphism, Single Nucleotide, Receptors, Interleukin-6 genetics, Receptors, Interleukin-6 immunology, Signal Transduction, Survival Rate, Transforming Growth Factor beta immunology, Aortic Aneurysm, Abdominal pathology, Receptors, Interleukin-6 metabolism
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.

Published
2019
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