Christian Herder1, Tonia de Las Heras Gala2, Maren Carstensen-Kirberg2, Cornelia Huth2, Astrid Zierer2, Simone Wahl2, Julie Sudduth-Klinger2, Kari Kuulasmaa2, David Peretz2, Symen Ligthart2, Brenda W C Bongaerts2, Abbas Dehghan2, M Arfan Ikram2, Antti Jula2, Frank Kee2, Arto Pietilä2, Olli Saarela2, Tanja Zeller2, Stefan Blankenberg2, Christa Meisinger2, Annette Peters2, Michael Roden2, Veikko Salomaa2, Wolfgang Koenig2, Barbara Thorand2. 1. From the Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany (C. Herder, M.C.-K., M.R.); German Center for Diabetes Research (DZD), München-Neuherberg, Germany (C. Herder, M.C.-K., A. Peters, M.R., B.T.); Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (T.d.l.H.G., C. Huth, A.Z., S.W., C.M., A. Peters, B.T.); German Center for Cardiovascular Research (DZHK), Partner site Munich Heart Alliance, Germany (T.d.l.H.G., W.K.); Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (S.W.); Tethys Bioscience, Emeryville, CA (J.S.-K., D.P.); National Institute for Health and Welfare, Helsinki, Finland (K.K., A. Pietilä, V.S.); Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands (S.L., A.D., M.A.I.); Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany (B.W.C.B.); Department of Biostatistics and Epidemiology, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, United Kingdom (A.D.); National Institute for Health and Welfare, Turku, Finland (A.J.); Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Institute of Clinical Science B, Queen's University Belfast, United Kingdom (F.K.); UKCRC Centre of Excellence for Public Health (Northern Ireland), Queen's University Belfast, United Kingdom (F.K.); Dalla Lana School of Public Health, University of Toronto, Ontario, Canada (O.S.); Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Germany (T.Z., S.B.); German Center for Cardiovascular Research (DZHK), Partner site Hamburg, Lübeck, Kiel, Germany (T.Z., S.B.); Department of Endocrinology and Diabetology, Medical Faculty, University Hospital Düsseldorf, Germany (M.R.); Deutsches Herzzentrum München, Technische Universität München, Germany (W.K.); and Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Germany (W.K.). christian.herder@ddz.uni-duesseldorf.de. 2. From the Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany (C. Herder, M.C.-K., M.R.); German Center for Diabetes Research (DZD), München-Neuherberg, Germany (C. Herder, M.C.-K., A. Peters, M.R., B.T.); Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (T.d.l.H.G., C. Huth, A.Z., S.W., C.M., A. Peters, B.T.); German Center for Cardiovascular Research (DZHK), Partner site Munich Heart Alliance, Germany (T.d.l.H.G., W.K.); Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (S.W.); Tethys Bioscience, Emeryville, CA (J.S.-K., D.P.); National Institute for Health and Welfare, Helsinki, Finland (K.K., A. Pietilä, V.S.); Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands (S.L., A.D., M.A.I.); Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany (B.W.C.B.); Department of Biostatistics and Epidemiology, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, United Kingdom (A.D.); National Institute for Health and Welfare, Turku, Finland (A.J.); Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Institute of Clinical Science B, Queen's University Belfast, United Kingdom (F.K.); UKCRC Centre of Excellence for Public Health (Northern Ireland), Queen's University Belfast, United Kingdom (F.K.); Dalla Lana School of Public Health, University of Toronto, Ontario, Canada (O.S.); Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Germany (T.Z., S.B.); German Center for Cardiovascular Research (DZHK), Partner site Hamburg, Lübeck, Kiel, Germany (T.Z., S.B.); Department of Endocrinology and Diabetology, Medical Faculty, University Hospital Düsseldorf, Germany (M.R.); Deutsches Herzzentrum München, Technische Universität München, Germany (W.K.); and Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Germany (W.K.).
Abstract
OBJECTIVE: Interleukin (IL)-1β represents a key cytokine in the development of cardiovascular disease (CVD). IL-1β is counter-regulated by IL-1 receptor antagonist (IL-1RA), an endogenous inhibitor. This study aimed to identify population-based studies on circulating IL-1RA and incident CVD in a systematic review, estimate the association between IL-1RA and incident CVD in a meta-analysis, and to test whether the association between IL-1RA and incident CVD is explained by other inflammation-related biomarkers in the MONICA/KORA Augsburg case-cohort study (Multinational Monitoring of Trends and Determinants in Cardiovascular Disease/Cooperative Health Research in the Region of Augsburg). APPROACH AND RESULTS: We performed a systematic literature search and identified 5 cohort studies on IL-1RA and incident CVD in addition to the MONICA/KORA Augsburg case-cohort study for a meta-analysis based on a total of 1855 CVD cases and 18 745 noncases with follow-up times between 5 and 16 years. The pooled standardized hazard ratio (95% confidence interval) for incident CVD was 1.11 (1.06-1.17) after adjustment for age, sex, anthropometric, metabolic, and lifestyle factors (P<0.0001). There was no heterogeneity in effect sizes (I2=0%; P=0.88). More detailed analyses in the MONICA/KORA study showed that the excess risk for CVD was attenuated by ≥10% after additional separate adjustment for serum levels of high-sensitivity C-reactive protein, IL-6, myeloperoxidase, soluble E-selectin, or soluble intercellular adhesion molecule-1. CONCLUSIONS: Serum IL-1RA levels were positively associated with risk of CVD after adjustment for multiple confounders in a meta-analysis of 6 population-based cohorts. This association may at least partially reflect a response to triggers inducing subclinical inflammation, oxidative stress, and endothelial activation.
OBJECTIVE: Interleukin (IL)-1β represents a key cytokine in the development of cardiovascular disease (CVD). IL-1β is counter-regulated by IL-1 receptor antagonist (IL-1RA), an endogenous inhibitor. This study aimed to identify population-based studies on circulating IL-1RA and incident CVD in a systematic review, estimate the association between IL-1RA and incident CVD in a meta-analysis, and to test whether the association between IL-1RA and incident CVD is explained by other inflammation-related biomarkers in the MONICA/KORA Augsburg case-cohort study (Multinational Monitoring of Trends and Determinants in Cardiovascular Disease/Cooperative Health Research in the Region of Augsburg). APPROACH AND RESULTS: We performed a systematic literature search and identified 5 cohort studies on IL-1RA and incident CVD in addition to the MONICA/KORA Augsburg case-cohort study for a meta-analysis based on a total of 1855 CVD cases and 18 745 noncases with follow-up times between 5 and 16 years. The pooled standardized hazard ratio (95% confidence interval) for incident CVD was 1.11 (1.06-1.17) after adjustment for age, sex, anthropometric, metabolic, and lifestyle factors (P<0.0001). There was no heterogeneity in effect sizes (I2=0%; P=0.88). More detailed analyses in the MONICA/KORA study showed that the excess risk for CVD was attenuated by ≥10% after additional separate adjustment for serum levels of high-sensitivity C-reactive protein, IL-6, myeloperoxidase, soluble E-selectin, or soluble intercellular adhesion molecule-1. CONCLUSIONS: Serum IL-1RA levels were positively associated with risk of CVD after adjustment for multiple confounders in a meta-analysis of 6 population-based cohorts. This association may at least partially reflect a response to triggers inducing subclinical inflammation, oxidative stress, and endothelial activation.
Authors: Ida T Fonkoue; Paul J Marvar; Seth Norrholm; Yunxiao Li; Melanie L Kankam; Toure N Jones; Monica Vemulapalli; Barbara Rothbaum; J Douglas Bremner; Ngoc-Anh Le; Jeanie Park Journal: Brain Behav Immun Date: 2019-11-01 Impact factor: 7.217
Authors: Antonio Abbate; Stefano Toldo; Carlo Marchetti; Jordana Kron; Benjamin W Van Tassell; Charles A Dinarello Journal: Circ Res Date: 2020-04-23 Impact factor: 17.367
Authors: Christian Stevns Hansen; Dorte Vistisen; Marit Eika Jørgensen; Daniel R Witte; Eric J Brunner; Adam G Tabák; Mika Kivimäki; Michael Roden; Marek Malik; Christian Herder Journal: Cardiovasc Diabetol Date: 2017-12-01 Impact factor: 9.951
Authors: Maren Carstensen-Kirberg; Julia M Kannenberg; Cornelia Huth; Christa Meisinger; Wolfgang Koenig; Margit Heier; Annette Peters; Wolfgang Rathmann; Michael Roden; Christian Herder; Barbara Thorand Journal: Cardiovasc Diabetol Date: 2017-08-29 Impact factor: 9.951
Authors: Cornelia Then; Christian Herder; Holger Then; Barbara Thorand; Cornelia Huth; Margit Heier; Christa Meisinger; Annette Peters; Wolfgang Koenig; Wolfgang Rathmann; Michael Roden; Michael Stumvoll; Haifa Maalmi; Thomas Meitinger; Andreas Lechner; Jürgen Scherberich; Jochen Seissler Journal: Clin Kidney J Date: 2020-09-06