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Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies

2012; Elsevier BV; Volume: 379; Issue: 9822 Linguagem: Inglês

10.1016/s0140-6736(11)61931-4

1474-547X

Nadeem Sarwar, Adam S. Butterworth, Daniel F. Freitag, John Gregson, Peter Willeit, Donal Gorman, Pei Gao, Danish Saleheen, Augusto Rendon, Christopher P. Nelson, Peter S. Braund, Alistair S. Hall, Daniel I. Chasman, Anne Tybjærg‐Hansen, John C. Chambers, Emelia J. Benjamin, Paul W. Franks, Robert Clarke, Arthur A.M. Wilde, Mieke D. Trip, Maristella Steri, Jacqueline C.M. Witteman, Lu Qi, C. Ellen van der Schoot, Ulf dé Fairé, Jeanette Erdmann, Heather M. Stringham, Wolfgang Köenig, Daniel J. Rader, David Melzer, David Reich, Bruce M. Psaty, Marcus E. Kleber, Demosthenes B. Panagiotakos, Johann Willeit, Patrik Wennberg, Mark Woodward, Svetlana Adamovic, Eric B. Rimm, Tom Meade, Richard F. Gillum, Jonathan A. Shaffer, Albert Hofman, Altan Onat, Johan Sundström, Sylvia Wassertheil‐Smoller, Dan Mellström, John Gallacher, Mary Cushman, Russell P. Tracy, Jussi Kauhanen, Magnus K. Karlsson, Jukka T. Salonen, Lars Wilhelmsen, Philippe Amouyel, Bernard Cantin, Lyle G. Best, Yoav Ben‐Shlomo, JoAnn E. Manson, George Davey Smith, Paul I. W. de Bakker, Christopher J. O’Donnell, Dragana Vuckovic, Anthony G. Wilson, Themistocles L. Assimes, John-Olov Jansson, Claes Ohlsson, Åsa Tivesten, Östen Ljunggren, Muredach P. Reilly, Anders Hamsten, Erik Ingelsson, François Cambien, Joseph Hung, G. Neil Thomas, Michael Boehnke, Heribert Schunkert, Folkert W. Asselbergs, John J.P. Kastelein, Vilmundur Guðnason, Veikko Salomaa, Tamara B. Harris, Jaspal S. Kooner, Kristine H. Allin, Børge G. Nordestgaard, Jemma C. Hopewell, Alison H. Goodall, Paul M. Ridker, Hilma Hólm, Hugh Watkins, Willem H. Ouwehand, N. J. Samani, Stephen Kaptoge, Emanuele Di Angelantonio, Olivier Harari, John Danesh,

Cytokine Signaling Pathways and Interactions

BackgroundPersistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling.MethodsIn a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6.FindingsThe minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3% (95% CI 30·4–38·2) and of interleukin 6 by 14·6% (10·7–18·4), and mean concentration of C-reactive protein was reduced by 7·5% (5·9–9·1) and of fibrinogen by 1·0% (0·7–1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4% (1·8–5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes.InterpretationLarge-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease.FundingBritish Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation.