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

Sarwar, Nadeem; Butterworth, Adam S.; Freitag, Daniel F.; Gregson, John; Willeit, Peter; Gorman, Donal N.; Gao, Pei; Saleheen, Danish; Rendon, Augusto and Nelson, Christopher P., et al. (2012) In The Lancet 379(9822). p.1205-1213
Abstract
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... (More)
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. (Less)
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The Lancet
volume
379
issue
9822
pages
1205 - 1213
publisher
Elsevier Limited
external identifiers
  • wos:000302230400033
  • scopus:84859210770
ISSN
1474-547X
DOI
10.1016/S0140-6736(11)61931-4
language
English
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yes
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9bfa4ba7-9466-4fc2-8d50-562fb12a8893 (old id 2494682)
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2012-05-07 14:32:48
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@article{9bfa4ba7-9466-4fc2-8d50-562fb12a8893,
  abstract     = {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.},
  author       = {Sarwar, Nadeem and Butterworth, Adam S. and Freitag, Daniel F. and Gregson, John and Willeit, Peter and Gorman, Donal N. and Gao, Pei and Saleheen, Danish and Rendon, Augusto and Nelson, Christopher P. and Braund, Peter S. and Hall, Alistair S. and Chasman, Daniel I. and Tybjaerg-Hansen, Anne and Chambers, John C. and Benjamin, Emelia J. and Franks, Paul and Clarke, Robert and Wilde, Arthur A. M. and Trip, Mieke D. and Steri, Maristella and Witteman, Jacqueline C. M. and Qi, Lu and van der Schoot, C. Ellen and de Faire, Ulf and Erdmann, Jeanette and Stringham, Heather M. and Koenig, Wolfgang and Rader, Daniel J. and Melzer, David and Reich, David and Psaty, Bruce M. and Kleber, Marcus E. and Panagiotakos, Demosthenes B. and Willeit, Johann and Wennberg, Patrik and Woodward, Mark and Adamovic, Svetlana and Rimm, Eric B. and Meade, Tom W. and Gillum, Richard F. and Shaffer, Jonathan A. and Hofman, Albert and Onat, Altan and Sundstrom, Johan and Wassertheil-Smoller, Sylvia and Mellstrom, Dan and Gallacher, John and Cushman, Mary and Tracy, Russell P. and Kauhanen, Jussi and Karlsson, Magnus and Salonen, Jukka T. and Wilhelmsen, Lars and Amouyel, Philippe and Cantin, Bernard and Best, Lyle G. and Ben-Shlomo, Yoav and Manson, JoAnn E. and Davey-Smith, George and de Bakker, Paul I. W. and O'Donnell, Christopher J. and Wilson, James F. and Wilson, Anthony G. and Assimes, Themistocles L. and Jansson, John-Olov and Ohlsson, Claes and Tivesten, Asa and Ljunggren, Osten and Reilly, Muredach P. and Hamsten, Anders and Ingelsson, Erik and Cambien, Francois and Hung, Joseph and Thomas, G. Neil and Boehnke, Michael and Schunkert, Heribert and Asselbergs, Folkert W. and Kastelein, John J. P. and Gudnason, Vilmundur and Salomaa, Veikko and Harris, Tamara B. and Kooner, Jaspal S. and Allin, Kristine H. and Nordestgaard, Borge G. and Hopewell, Jemma C. and Goodall, Alison H. and Ridker, Paul M. and Holm, Hilma and Watkins, Hugh and Ouwehand, Willem H. and Samani, Nilesh J. and Kaptoge, Stephen and Di Angelantonio, Emanuele and Harari, Olivier and Danesh, John},
  issn         = {1474-547X},
  language     = {eng},
  number       = {9822},
  pages        = {1205--1213},
  publisher    = {Elsevier Limited},
  series       = {The Lancet},
  title        = {Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies},
  url          = {http://dx.doi.org/10.1016/S0140-6736(11)61931-4},
  volume       = {379},
  year         = {2012},
}