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

doi: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

School of management

Research output: Contribution to journal › Article › peer-review

679 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 language	English
Pages (from-to)	1205-1213
Number of pages	9
Journal	The Lancet
Volume	379
Issue number	9822
DOIs	https://doi.org/10.1016/S0140-6736(11)61931-4
Publication status	Published - Mar 1 2012

ASJC Scopus Subject Areas

General Medicine

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10.1016/S0140-6736(11)61931-4

Cite this

@article{e367a0f16a3a46d3b1e6169e58589ebf,

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

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.",

author = "{Members of the IL6R Genetics Consortium and the Emerging Risk Factors Collaboration} and Nadeem Sarwar and Butterworth, {Adam S.} and Freitag, {D. F.} and J. Gregson and P. Willeit and Gorman, {D. N.} and P. Gao and D. Saleheen and A. Rendon and Nelson, {C. P.} and Braund, {P. S.} and Hall, {A. S.} and Chasman, {D. I.} and A. Tybj{\ae}rg-Hansen and Chambers, {J. C.} and Benjamin, {E. J.} and Franks, {P. W.} and R. Clarke and Wilde, {A. A.} and Trip, {M. D.} and M. Steri and Witteman, {J. C.} and L. Qi and {van der Schoot}, {C. E.} and {de Faire}, U. and J. Erdmann and Stringham, {H. M.} and W. Koenig and Rader, {D. J.} and D. Melzer and D. Reich and Psaty, {B. M.} and Kleber, {M. E.} and Panagiotakos, {D. B.} and J. Willeit and P. Wennberg and M. Woodward and S. Adamovic and Rimm, {E. B.} and Meade, {T. W.} and Gillum, {R. F.} and Shaffer, {J. A.} and A. Hofman and A. Onat and J. Sundstr{\"o}m and S. Wassertheil-Smoller and D. Mellstr{\"o}m and J. Gallacher and M. Cushman and Tracy, {R. P.} and J. Kauhanen and M. Karlsson and Salonen, {J. T.} and L. Wilhelmsen and P. Amouyel and B. Cantin and Best, {L. G.} and Y. Ben-Shlomo and Manson, {J. E.} and G. Davey-Smith and {de Bakker}, {P. I.} and O'Donnell, {C. J.} and Wilson, {J. F.} and Wilson, {A. G.} and Assimes, {T. L.} and Jansson, {John Olov} and C. Ohlsson and {\AA}sa Tivesten and Ljunggren and Reilly, {M. P.} and A. Hamsten and E. Ingelsson and F. Cambien and J. Hung and Thomas, {G. N.} and M. Boehnke and H. Schunkert and Asselbergs, {F. W.} and Kastelein, {J. J.P.} and V. Gudnason and V. Salomaa and Harris, {T. B.} and Kooner, {J. S.} and Allin, {K. H.} and Nordestgaard, {B. G.} and Hopewell, {J. C.} and Goodall, {A. H.} and Ridker, {P. M.} and H. H{\'o}lm and H. Watkins and Ouwehand, {W. H.} and Samani, {N. J.} and S. Kaptoge and {Di Angelantonio}, E. and O. Harari and J. Danesh and Thomas Quertermous and Go, {Alan S.} and Hlatky, {Mark A.} and Knowles, {Joshua W.} and Smith, {Albert V.} and Christina Chrysohoou and Christos Pitsavos and Christodoulos Stefanadis and Balmforth, {Anthony J.} and Thompson, {John R.} and {Ellen van der Schoot}, C. and Suthesh Sivapalaratnam and Stephani Maiwald and Hanneke Basart and Mahdi Motazacker and {de Jong}, {Jonas S.S.G.} and Dekker, {Lucas R.C.} and Michael Tanck and Bezzina, {Connie R.} and Whincup, {Peter H.} and Morris, {Richard W.} and {Goya Wannamethee}, S. and Stefan Kiechl and Yarnell, {John W.G.} and Gordon Lowe and Ann Rumley and Mukamal, {Kenneth J.} and Havulinna, {Aki S.} and Lokki, {Marja Liisa} and Nieminen, {Markku S.} and Samuli Ripatti and Juha Sinisalo and McQuillan, {Brendan M.} and Beilby, {John P.} and Thompson, {Peter L.} and Gu{\dh}mar Thorleifsson and Gu{\dh}mundur Thorgeirsson and Unnur Thorsteinsd{\'o}ttir and Kari Stefansson and Antti Jula and Satu M{\"a}nnist{\"o} and Markus Perola and Emmi Tikkanen and Boer, {Jolanda M.A.} and Onland-Moret, {N. Charlotte} and {van der Schouw}, {Yvonne T.} and {Monique Verschuren}, {W. M.} and Jansson, {Jan H{\aa}kan} and Jos{\'e}e Dupuis and Fontes, {Jo{\~a}o D.} and Xiaoyan Yin and O{\textquoteright}Donnell, {Christopher J.} and Jaakko Tuomilehto and Koenig, {Inke R.} and Janja Nahrstaedt and Christina Loley and Klaus Stark and Christina Willenborg and Christian Hengstenberg and Stefan Schreiber and Michael Preuss and In{\^e}s Barroso and G{\"o}ran Hallmans and Dmitry Shungin and {Keung Cheng}, Kar and {Hing Lam}, Tai and {Chiang Jiang}, Chao and Jennifer Pai and Rory Collins and Sarah Parish and Jane Armitage and Anne Jackson and Kristian Hveem and Wiggins, {Kerri L.} and Heckbert, {Susan R.} and Smith, {Nicholas L.} and Bis, {Joshua C.} and Luigi Ferrucci and Guralnik, {Jack M.} and Stefania Bandinelli and Singleton, {Andrew B.} and Tuomainen, {Tomi Pekka} and Sudhir Kurl and Weihua Zhang and Kooner, {Angad S.} and Debashis Das and Winfried M{\"a}rz and Hubert Scharnagl and B{\"o}hm, {Bernhard O.} and Winkelmann, {Bernhard R.} and Folsom, {Aaron R.} and Shea, {Steven J.} and Markku Laakso and Johanna Kuusisto and Jens Baumert and Barbara Thorand and Thomas Illig and Christa Meisinger and Annika Rosengren and Karlsson, {Magnus K.} and Hu, {Frank B.} and Hankinson, {Susan E.} and Davidson, {Karina W.} and Ross Fraser and Sarah Wild and Harry Campbell and Atif Qasim and Liming Qu and Mingyao Li and Lars Lind and Syv{\"a}nen, {Ann Christine} and Dominique Arveiler and Martin Farrall and Peden, {John F.} and Panos Deloukas and Nasir Sheikh and Asif Rasheed and Dagenais, {Gilles R.} and Abbas Dehghan and {van Duijn}, {Cornelia M.} and Uitterlinden, {Andre G.} and Abecasis, {Goncalo R.} and Francesco Cucca and Serena Sanna and Manuela Uda and David Schlessinger and Maria Sabater-Lleal and Angela Silveira and Bruna Gigante and Howard, {Barbara V.} and Samar Basu and Rose, {Lynda M.} and Julie Buring",

year = "2012",

month = mar,

day = "1",

doi = "10.1016/S0140-6736(11)61931-4",

language = "English",

volume = "379",

pages = "1205--1213",

journal = "The Lancet",

issn = "0140-6736",

publisher = "Elsevier B.V.",

number = "9822",

}

TY - JOUR

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 - Tracy, R. P.

AU - Kauhanen, J.

AU - Karlsson, M.

AU - Salonen, J. T.

AU - Wilhelmsen, L.

AU - Amouyel, P.

AU - Cantin, B.

AU - Best, L. G.

AU - Ben-Shlomo, Y.

AU - Manson, J. E.

AU - Davey-Smith, G.

AU - de Bakker, P. I.

AU - O'Donnell, C. J.

AU - Wilson, J. F.

AU - Wilson, A. G.

AU - Assimes, T. L.

AU - Jansson, John Olov

AU - Ohlsson, C.

AU - Tivesten, Åsa

AU - Ljunggren,

AU - Reilly, M. P.

AU - Hamsten, A.

AU - Ingelsson, E.

AU - Cambien, F.

AU - Hung, J.

AU - Thomas, G. N.

AU - Boehnke, M.

AU - Schunkert, H.

AU - Asselbergs, F. W.

AU - Kastelein, J. J.P.

AU - Gudnason, V.

AU - Salomaa, V.

AU - Harris, T. B.

AU - Kooner, J. S.

AU - Allin, K. H.

AU - Nordestgaard, B. G.

AU - Hopewell, J. C.

AU - Goodall, A. H.

AU - Ridker, P. M.

AU - Hólm, H.

AU - Watkins, H.

AU - Ouwehand, W. H.

AU - Samani, N. J.

AU - Kaptoge, S.

AU - Di Angelantonio, E.

AU - Harari, O.

AU - Danesh, J.

AU - Quertermous, Thomas

AU - Go, Alan S.

AU - Hlatky, Mark A.

AU - Knowles, Joshua W.

AU - Smith, Albert V.

AU - Chrysohoou, Christina

AU - Pitsavos, Christos

AU - Stefanadis, Christodoulos

AU - Balmforth, Anthony J.

AU - Thompson, John R.

AU - Ellen van der Schoot, C.

AU - Sivapalaratnam, Suthesh

AU - Maiwald, Stephani

AU - Basart, Hanneke

AU - Motazacker, Mahdi

AU - de Jong, Jonas S.S.G.

AU - Dekker, Lucas R.C.

AU - Tanck, Michael

AU - Bezzina, Connie R.

AU - Whincup, Peter H.

AU - Morris, Richard W.

AU - Goya Wannamethee, S.

AU - Kiechl, Stefan

AU - Yarnell, John W.G.

AU - Lowe, Gordon

AU - Rumley, Ann

AU - Mukamal, Kenneth J.

AU - Havulinna, Aki S.

AU - Lokki, Marja Liisa

AU - Nieminen, Markku S.

AU - Ripatti, Samuli

AU - Sinisalo, Juha

AU - McQuillan, Brendan M.

AU - Beilby, John P.

AU - Thompson, Peter L.

AU - Thorleifsson, Guðmar

AU - Thorgeirsson, Guðmundur

AU - Thorsteinsdóttir, Unnur

AU - Stefansson, Kari

AU - Jula, Antti

AU - Männistö, Satu

AU - Perola, Markus

AU - Tikkanen, Emmi

AU - Boer, Jolanda M.A.

AU - Onland-Moret, N. Charlotte

AU - van der Schouw, Yvonne T.

AU - Monique Verschuren, W. M.

AU - Jansson, Jan Håkan

AU - Dupuis, Josée

AU - Fontes, João D.

AU - Yin, Xiaoyan

AU - O’Donnell, Christopher J.

AU - Tuomilehto, Jaakko

AU - Koenig, Inke R.

AU - Nahrstaedt, Janja

AU - Loley, Christina

AU - Stark, Klaus

AU - Willenborg, Christina

AU - Hengstenberg, Christian

AU - Schreiber, Stefan

AU - Preuss, Michael

AU - Barroso, Inês

AU - Hallmans, Göran

AU - Shungin, Dmitry

AU - Keung Cheng, Kar

AU - Hing Lam, Tai

AU - Chiang Jiang, Chao

AU - Pai, Jennifer

AU - Collins, Rory

AU - Parish, Sarah

AU - Armitage, Jane

AU - Jackson, Anne

AU - Hveem, Kristian

AU - Wiggins, Kerri L.

AU - Heckbert, Susan R.

AU - Smith, Nicholas L.

AU - Bis, Joshua C.

AU - Ferrucci, Luigi

AU - Guralnik, Jack M.

AU - Bandinelli, Stefania

AU - Singleton, Andrew B.

AU - Tuomainen, Tomi Pekka

AU - Kurl, Sudhir

AU - Zhang, Weihua

AU - Kooner, Angad S.

AU - Das, Debashis

AU - März, Winfried

AU - Scharnagl, Hubert

AU - Böhm, Bernhard O.

AU - Winkelmann, Bernhard R.

AU - Folsom, Aaron R.

AU - Shea, Steven J.

AU - Laakso, Markku

AU - Kuusisto, Johanna

AU - Baumert, Jens

AU - Thorand, Barbara

AU - Illig, Thomas

AU - Meisinger, Christa

AU - Rosengren, Annika

AU - Karlsson, Magnus K.

AU - Hu, Frank B.

AU - Hankinson, Susan E.

AU - Davidson, Karina W.

AU - Fraser, Ross

AU - Wild, Sarah

AU - Campbell, Harry

AU - Qasim, Atif

AU - Qu, Liming

AU - Li, Mingyao

AU - Lind, Lars

AU - Syvänen, Ann Christine

AU - Arveiler, Dominique

AU - Farrall, Martin

AU - Peden, John F.

AU - Deloukas, Panos

AU - Sheikh, Nasir

AU - Rasheed, Asif

AU - Dagenais, Gilles R.

AU - Dehghan, Abbas

AU - van Duijn, Cornelia M.

AU - Uitterlinden, Andre G.

AU - Abecasis, Goncalo R.

AU - Cucca, Francesco

AU - Sanna, Serena

AU - Uda, Manuela

AU - Schlessinger, David

AU - Sabater-Lleal, Maria

AU - Silveira, Angela

AU - Gigante, Bruna

AU - Howard, Barbara V.

AU - Basu, Samar

AU - Rose, Lynda M.

AU - Buring, Julie

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.

UR - http://www.scopus.com/inward/record.url?scp=84859210770&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84859210770&partnerID=8YFLogxK

U2 - 10.1016/S0140-6736(11)61931-4

DO - 10.1016/S0140-6736(11)61931-4

M3 - Article

C2 - 22421339

AN - SCOPUS:84859210770

SN - 0140-6736

VL - 379

SP - 1205

EP - 1213

JO - The Lancet

JF - The Lancet

IS - 9822

ER -

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

Abstract

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