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Meta-Analysis
. 2012 Mar 31;379(9822):1205-13.
doi: 10.1016/S0140-6736(11)61931-4. Epub 2012 Mar 14.

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

IL6R Genetics Consortium Emerging Risk Factors Collaboration; 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 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 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 Sundström, Sylvia Wassertheil-Smoller, Dan Mellström, 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, Åsa Tivesten, Östen 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, Børge G Nordestgaard, Jemma C Hopewell, Alison H Goodall, Paul M Ridker, Hilma Hólm, Hugh Watkins, Willem H Ouwehand, Nilesh J Samani, Stephen Kaptoge, Emanuele Di Angelantonio, Olivier Harari, John Danesh
Collaborators
Meta-Analysis

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

IL6R Genetics Consortium Emerging Risk Factors Collaboration et al. Lancet. .

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.

Funding: British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation.

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Figures

Figure 1
Figure 1
IL6R genotypes and circulating concentrations of inflammation markers Analyses were undertaken with standardised units of measurement for each marker. To enable comparison of the magnitude of associations across several different markers, associations are presented as percentage differences (calculated in reference to the weighted overall mean of each marker among the reference group). The number of participants with information about each marker is shown in the table. Details of the genotypes studied are provided in appendix p 12. Error bars show 95% CI. IL6R=interleukin-6 receptor. *Reference group (represented by a square with an arbitrary fixed size).
Figure 2
Figure 2
IL6R genotypes and risk of coronary heart disease Data are shown for 51 441 cases and 136 226 controls. The odds ratio per minor allele was 0·966 (95% CI 0·950–0·982, p=4·5×10−5). Details of the genotypes studied are provided in appendix p 12. Error bars show 95% CI. *Reference group (represented by a square with in arbitrary fixed size).
Figure 3
Figure 3
(A) Cross-sectional associations between interleukin 6, C-reactive protein, and fibrinogen concentrations in the general population and (B) associations of interleukin 6, C-reactive protein, and fibrinogen concentrations with incident coronary heart disease Adjusted for age, sex, smoking, body-mass index, diabetes status, systolic blood pressure, and total cholesterol. Studies included in these analyses had information on at least two of the biomarkers studied and had recorded at least ten incident coronary heart disease events during follow-up. Error bars show 95% CI.
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Comment in

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