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 Jan 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

Research output: Contribution to journalArticle

4 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 (US)
Pages (from-to)e002413
JournalCirculation. Genomic and precision medicine
Volume12
Issue number2
DOIs
StatePublished - Feb 1 2019

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Interleukin-6 Receptors
Abdominal Aortic Aneurysm
Growth
Interleukin-6
Aortic Rupture
Aneurysm
Linear Models
Alleles
Blood Pressure
Aortic Aneurysm
Dissection
Biomarkers

Keywords

  • alleles
  • aortic aneurysm
  • genetics
  • inflammation
  • interleukins

Cite this

Paige, E., Clément, M., Lareyre, F., Sweeting, M., Raffort, J., Grenier, C., ... Mallat, Z. (2019). Interleukin-6 Receptor Signaling and Abdominal Aortic Aneurysm Growth Rates. Circulation. Genomic and precision medicine, 12(2), e002413. https://doi.org/10.1161/CIRCGEN.118.002413

Interleukin-6 Receptor Signaling and Abdominal Aortic Aneurysm Growth Rates. / Paige, Ellie; Clément, Marc; Lareyre, Fabien; Sweeting, Michael; Raffort, Juliette; Grenier, Céline; Finigan, Alison; Harrison, James; Peters, James E.; Sun, Benjamin B.; Butterworth, Adam S.; Harrison, Seamus C.; Bown, Matthew J.; Lindholt, Jes S.; Badger, Stephen A.; Kullo, Iftikhar Jan; Powell, Janet; Norman, Paul E.; Scott, D. Julian A.; Bailey, Marc A.; Rose-John, Stefan; Danesh, John; Freitag, Daniel F.; Paul, Dirk S.; Mallat, Ziad.

In: Circulation. Genomic and precision medicine, Vol. 12, No. 2, 01.02.2019, p. e002413.

Research output: Contribution to journalArticle

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 & Mallat, Z 2019, 'Interleukin-6 Receptor Signaling and Abdominal Aortic Aneurysm Growth Rates', Circulation. Genomic and precision medicine, vol. 12, no. 2, pp. e002413. https://doi.org/10.1161/CIRCGEN.118.002413
Paige, Ellie ; Clément, Marc ; Lareyre, Fabien ; Sweeting, Michael ; Raffort, Juliette ; Grenier, Céline ; Finigan, Alison ; Harrison, James ; Peters, James E. ; Sun, Benjamin B. ; Butterworth, Adam S. ; Harrison, Seamus C. ; Bown, Matthew J. ; Lindholt, Jes S. ; Badger, Stephen A. ; Kullo, Iftikhar Jan ; Powell, Janet ; Norman, Paul E. ; Scott, D. Julian A. ; Bailey, Marc A. ; Rose-John, Stefan ; Danesh, John ; Freitag, Daniel F. ; Paul, Dirk S. ; Mallat, Ziad. / Interleukin-6 Receptor Signaling and Abdominal Aortic Aneurysm Growth Rates. In: Circulation. Genomic and precision medicine. 2019 ; Vol. 12, No. 2. pp. e002413.
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AU - Paige, Ellie

AU - Clément, Marc

AU - Lareyre, Fabien

AU - Sweeting, Michael

AU - Raffort, Juliette

AU - Grenier, Céline

AU - Finigan, Alison

AU - Harrison, James

AU - Peters, James E.

AU - Sun, Benjamin B.

AU - Butterworth, Adam S.

AU - Harrison, Seamus C.

AU - Bown, Matthew J.

AU - Lindholt, Jes S.

AU - Badger, Stephen A.

AU - Kullo, Iftikhar Jan

AU - Powell, Janet

AU - Norman, Paul E.

AU - Scott, D. Julian A.

AU - Bailey, Marc A.

AU - Rose-John, Stefan

AU - Danesh, John

AU - Freitag, Daniel F.

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N2 - 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.

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