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

Members of the IL6R Genetics Consortium and the Emerging Risk Factors Collaboration

Research output: Contribution to journalArticle

385 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1205-1213
Number of pages9
JournalThe Lancet
Volume379
Issue number9822
DOIs
StatePublished - Mar 1 2012
Externally publishedYes

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Interleukin-6 Receptors
Coronary Disease
Meta-Analysis
Interleukin-6
Inflammation
Biomedical Research
Biomarkers
Adiposity
National Institutes of Health (U.S.)
Medical Genetics
Gene Frequency
C-Reactive Protein
Fibrinogen
Monocytes
Cardiovascular Diseases
Smoking
Alleles
Blood Pressure
Lipids
Gene Expression

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Members of the IL6R Genetics Consortium and the Emerging Risk Factors Collaboration (2012). Interleukin-6 receptor pathways in coronary heart disease: A collaborative meta-analysis of 82 studies. The Lancet, 379(9822), 1205-1213. https://doi.org/10.1016/S0140-6736(11)61931-4

Interleukin-6 receptor pathways in coronary heart disease : A collaborative meta-analysis of 82 studies. / Members of the IL6R Genetics Consortium and the Emerging Risk Factors Collaboration.

In: The Lancet, Vol. 379, No. 9822, 01.03.2012, p. 1205-1213.

Research output: Contribution to journalArticle

Members of the IL6R Genetics Consortium and the Emerging Risk Factors Collaboration 2012, 'Interleukin-6 receptor pathways in coronary heart disease: A collaborative meta-analysis of 82 studies', The Lancet, vol. 379, no. 9822, pp. 1205-1213. https://doi.org/10.1016/S0140-6736(11)61931-4
Members of the IL6R Genetics Consortium and the Emerging Risk Factors Collaboration. Interleukin-6 receptor pathways in coronary heart disease: A collaborative meta-analysis of 82 studies. The Lancet. 2012 Mar 1;379(9822):1205-1213. https://doi.org/10.1016/S0140-6736(11)61931-4
Members of the IL6R Genetics Consortium and the Emerging Risk Factors Collaboration. / Interleukin-6 receptor pathways in coronary heart disease : A collaborative meta-analysis of 82 studies. In: The Lancet. 2012 ; Vol. 379, No. 9822. pp. 1205-1213.
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T1 - Interleukin-6 receptor pathways in coronary heart disease

T2 - A collaborative meta-analysis of 82 studies

AU - Members of the IL6R Genetics Consortium and the Emerging Risk Factors Collaboration

AU - Sarwar, Nadeem

AU - Butterworth, Adam S.

AU - Freitag, D. F.

AU - Gregson, J.

AU - Willeit, P.

AU - Gorman, D. N.

AU - Gao, P.

AU - Saleheen, D.

AU - Rendon, A.

AU - Nelson, C. P.

AU - Braund, P. S.

AU - Hall, A. S.

AU - Chasman, D. I.

AU - Tybjærg-Hansen, A.

AU - Chambers, J. C.

AU - Benjamin, E. J.

AU - Franks, P. W.

AU - Clarke, R.

AU - Wilde, A. A.

AU - Trip, M. D.

AU - Steri, M.

AU - Witteman, J. C.

AU - Qi, L.

AU - van der Schoot, C. E.

AU - de Faire, U.

AU - Erdmann, J.

AU - Stringham, H. M.

AU - Koenig, W.

AU - Rader, D. J.

AU - Melzer, D.

AU - Reich, D.

AU - Psaty, B. M.

AU - Kleber, M. E.

AU - Panagiotakos, D. B.

AU - Willeit, J.

AU - Wennberg, P.

AU - Woodward, M.

AU - Adamovic, S.

AU - Rimm, E. B.

AU - Meade, T. W.

AU - Gillum, R. F.

AU - Shaffer, J. A.

AU - Hofman, A.

AU - Onat, A.

AU - Sundström, J.

AU - Wassertheil-Smoller, S.

AU - Mellström, D.

AU - Gallacher, J.

AU - Cushman, M.

AU - Fontes, Joao Daniel T.

PY - 2012/3/1

Y1 - 2012/3/1

N2 - 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.

AB - 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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