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

Author:
  • Nadeem Sarwar
  • Adam S. Butterworth
  • Daniel F. Freitag
  • John Gregson
  • Peter Willeit
  • Donal N. Gorman
  • Pei Gao
  • Danish Saleheen
  • Augusto Rendon
  • Christopher P. Nelson
  • Peter S. Braund
  • Alistair S. Hall
  • Daniel I. Chasman
  • Anne Tybjaerg-Hansen
  • John C. Chambers
  • Emelia J. Benjamin
  • Paul Franks
  • Robert Clarke
  • Arthur A. M. Wilde
  • Mieke D. Trip
  • Maristella Steri
  • Jacqueline C. M. Witteman
  • Lu Qi
  • C. Ellen van der Schoot
  • Ulf de Faire
  • Jeanette Erdmann
  • Heather M. Stringham
  • Wolfgang Koenig
  • 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 W. Meade
  • Richard F. Gillum
  • Jonathan A. Shaffer
  • Albert Hofman
  • Altan Onat
  • Johan Sundstrom
  • Sylvia Wassertheil-Smoller
  • Dan Mellstrom
  • John Gallacher
  • Mary Cushman
  • Russell P. Tracy
  • Jussi Kauhanen
  • Magnus 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
  • James F. Wilson
  • Anthony G. Wilson
  • Themistocles L. Assimes
  • John-Olov Jansson
  • Claes Ohlsson
  • Asa Tivesten
  • Osten Ljunggren
  • Muredach P. Reilly
  • Anders Hamsten
  • Erik Ingelsson
  • Francois Cambien
  • Joseph Hung
  • G. Neil Thomas
  • Michael Boehnke
  • Heribert Schunkert
  • Folkert W. Asselbergs
  • John J. P. Kastelein
  • Vilmundur Gudnason
  • Veikko Salomaa
  • Tamara B. Harris
  • Jaspal S. Kooner
  • Kristine H. Allin
  • Borge G. Nordestgaard
  • Jemma C. Hopewell
  • Alison H. Goodall
  • Paul M. Ridker
  • Hilma Holm
  • Hugh Watkins
  • Willem H. Ouwehand
  • Nilesh J. Samani
  • Stephen Kaptoge
  • Emanuele Di Angelantonio
  • Olivier Harari
  • John Danesh
Publishing year: 2012
Language: English
Pages: 1205-1213
Publication/Series: The Lancet
Volume: 379
Issue: 9822
Document type: Journal article
Publisher: Elsevier Limited

Abstract english

Background Persistent 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. Methods In 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. Findings The 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. Interpretation Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease.

Keywords

  • Endocrinology and Diabetes
  • Orthopedics

Other

Published
  • Genetic and Molecular Epidemiology
  • Clinical and Molecular Osteoporosis Research
  • ISSN: 1474-547X
Paul Franks
E-mail: paul.franks [at] med.lu.se

Principal investigator

Genetic and Molecular Epidemiology

+46 40 39 11 49

60-12-021

33

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