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

Nadeem Sarwar; Adam S. Butterworth; D. F. Freitag; J. Gregson; P. Willeit; D. N. Gorman; P. Gao; D. Saleheen; A. Rendon; C. P. Nelson; P. S. Braund; A. S. Hall; D. I. Chasman; A. Tybjærg-Hansen; J. C. Chambers; E. J. Benjamin; P. W. Franks; R. Clarke; A. A. Wilde; M. D. Trip; M. Steri; J. C. Witteman; L. Qi; C. E. van der Schoot; U. de Faire; J. Erdmann; H. M. Stringham; W. Koenig; D. J. Rader; D. Melzer; D. Reich; B. M. Psaty; M. E. Kleber; D. B. Panagiotakos; J. Willeit; P. Wennberg; M. Woodward; S. Adamovic; E. B. Rimm; T. W. Meade; R. F. Gillum; J. A. Shaffer; A. Hofman; A. Onat; J. Sundström; S. Wassertheil-Smoller; D. Mellström; H. Schunkert; Christina Willenborg; Members of the IL6R Genetics Consortium and the Emerging Risk Factors Collaboration; Michael Preuss

doi:10.1016/S0140-6736(11)61931-4

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

Nadeem Sarwar^*, Adam S. Butterworth, D. F. Freitag, J. Gregson, P. Willeit, D. N. Gorman, P. Gao, D. Saleheen, A. Rendon, C. P. Nelson, P. S. Braund, A. S. Hall, D. I. Chasman, A. Tybjærg-Hansen, J. C. Chambers, E. J. Benjamin, P. W. Franks, R. Clarke, A. A. Wilde, M. D. TripM. Steri, J. C. Witteman, L. Qi, C. E. van der Schoot, U. de Faire, J. Erdmann, H. M. Stringham, W. Koenig, D. J. Rader, D. Melzer, D. Reich, B. M. Psaty, M. E. Kleber, D. B. Panagiotakos, J. Willeit, P. Wennberg, M. Woodward, S. Adamovic, E. B. Rimm, T. W. Meade, R. F. Gillum, J. A. Shaffer, A. Hofman, A. Onat, J. Sundström, S. Wassertheil-Smoller, D. Mellström, H. Schunkert, Christina Willenborg, Members of the IL6R Genetics Consortium and the Emerging Risk Factors Collaboration, Michael Preuss

^*Corresponding author for this work

University of Cambridge

724 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
Journal	The Lancet
Volume	379
Issue number	9822
Pages (from-to)	1205-1213
Number of pages	9
ISSN	0140-6736
DOIs	https://doi.org/10.1016/S0140-6736(11)61931-4
Publication status	Published - 01.03.2012

Funding

Interest in the inflammation hypothesis of cardiovascular disease has intensified since the launch of phase 3 trials of various anti-inflammatory agents in the secondary prevention of cardiovascular disease, including two trials of darapladib (an inhibitor of lipoprotein-associated phospholipase A 2 ), 31 a trial of canakinumab (a monoclonal antibody to interleukin 1β), 32 and a trial of low-dose methotrexate. 33 Although this hypothesis has received some support from previous human genetic studies that implicate loci of potential relevance to inflammation, including CXCL12 , 34 ADAMTS7 , 35 SH2B3 , 34 and IL5 , 23 in coronary heart disease, such studies have not provided specific insight into inflammation and coronary heart disease because the relevant genes (or causal alleles) in these loci still await identification. By contrast, the present study has focused on a specific functional allele known to affect IL6R signalling. This meta-analysis has provided large-scale human genetic and biomarker evidence that is consistent with a causal association between IL6R-related pathways and coronary heart disease ( ). First, our results have shown that Asp358Ala—a common functional variant in panel IL6R —is unrelated to a panel of conventional cardiovascular disease risk factors, suggesting that any effect of Asp358Ala on risk of coronary heart disease is unlikely to be mediated by conventional risk factors. Second, we noted that carriage of 358Ala was associated, in a dose-dependent manner, with decreased concentrations of C-reactive protein and fibrinogen (two different liver-derived proteins that sensitively reflect inflammation status), suggesting that 358Ala dampens the systemic inflammatory response. 22 Third, our results show that 358Ala is significantly related to decreased risk of coronary heart disease in the same dose-dependent manner. In aggregate, therefore, these results support the inflammation hypothesis in coronary heart disease and encourage exploration of modulation of IL6R pathways as a means to prevent coronary heart disease. Our study has confirmed previous reports of positive associations between circulating interleukin-6 concentration and subsequent risk of coronary heart disease. 3,36 That 358Ala, which is inversely related to coronary heart disease, is strongly related with higher concentrations of both soluble IL6R and interleukin 6 in a dose-dependent manner might, therefore, seem paradoxical. However, this apparent paradox might be resolved by previous suggestions that 358Ala impairs classical IL6R signalling by reducing membrane-bound IL6R levels, either through increased receptor shedding or alternative splicing, rather than by changes in production of IL6R or interleukin 6. 11–14 Such mechanisms could account for the accumulation of both soluble IL6R and interleukin 6 in the circulation of people who carry 358Ala. It would also be consistent with two findings in our study. First, expression analyses showed that Asp358Ala was not associated with interleukin-6 production in several different tissues or in monocytes after lipopolysaccharide stimulation. Second, whereas we reported positive interrelations among circulating concentrations of interleukin 6, C-reactive protein, and fibrinogen with one another in the general population, carriage of 358Ala was associated with increased interleukin 6 but decreased C-reactive protein and fibrinogen concentrations. Nevertheless, further mechanistic studies are needed to improve understanding of these findings. For example, investigation of 358Ala in relation to other inflammation-related phenotypes (and its potential effects on gp130-mediated trans-signalling) to further understand its pleiotropic immunomodulatory effects would be of particular interest in view of the recently reported association of 358Ala with an increased risk of asthma. 20 Pharmacological agents such as tocilizumab, an antihuman monoclonal antibody that competitively inhibits IL6R, reduce circulating concentrations of downstream inflammation biomarkers and produce clinical benefits in rheumatoid arthritis and in other inflammatory conditions. 37,38 There have also been suggestions that such agents improve endothelial function in arthritis patients and reduce atherosclerosis in mice. 39,40 However, whether these agents affect risk of coronary heart disease is not yet known. Our meta-analysis confirms that tocilizumab use in patients with inflammatory conditions increases LDL and HDL cholesterol and triglyceride concentrations. It is uncertain whether such lipid changes reflect improvements in underlying chronic inflammation with tocilizumab, mechanism-based effects of IL6R modification, or tocilizumab-specific effects. 41–43 Hence, the US Food and Drug Administration has mandated further study of tocilizumab and cardiovascular disease risk factors in postmarketing clinical trials. 44 Increases in LDL cholesterol with tocilizumab might be avoidable, or at least attenuated, with concomitant statin use. 45,46 However, as shown by our meta-analysis, carriage of 358Ala is unrelated to concentrations of major lipids, suggesting that interleukin-6 modulation might not inherently increase these lipids. Further work is needed to understand why the effect of tocilizumab on major lipids differs from that of Asp358Ala, despite directionally consistent effects on inflammation biomarkers. The generalisability and validity of our findings have been improved by our analysis of genetic and biomarker data for more than 200 000 participants. Our observation of an association between a single functional variant in IL6R and coronary heart disease has been supported by a recent replication study of a genome-wide association scan. 47 By analogy with the fairly small effects of common variants in LDLR on coronary heart disease still being compatible with the major benefits of statins in coronary heart disease, 48 the effect of 358Ala on coronary heart disease does not necessarily restrict the scope for potential therapeutic effect of IL6R modification in coronary heart disease. 49 Future studies will seek to study Asp358Ala (or lower frequency variants with more pronounced effects) in relation to additional traits, non-coronary heart disease outcomes, and expression studies involving multiple cell types. Although our study involves the principle of mendelian randomisation, we did not do an instrumental variables analysis for two reasons: first, the relevant intermediate phenotype of the IL6R pathway remains uncertain because Asp358Ala is associated with changes in several inflammation biomarkers; second, our study was limited to aggregated (rather than individual-level) genetic data. In conclusion, our data support a causal association between IL6R-related pathways and coronary heart disease. Correspondence to: Dr Nadeem Sarwar or Dr Adam S Butterworth, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK [email protected] Contributors Nadeem Sarwar, Adam Butterworth, and John Danesh drafted the report. Nadeem Sarwar, Adam Butterworth, Pei Gao, Daniel Freitag, Donal Gorman, Peter Willeit, John Gregson, Danish Saleheen, Stephen Kaptoge, and Emanuele Di Angelantonio undertook literature searches and analysed data. Augusto Rendon, Christopher Nelson, and Peter Braund also analysed data. All investigators shared data and had opportunities to contribute to the interpretation of the results and critical revision of the report. All members of the writing committee provided critical revisions. All members of the coordinating centre contributed to the collection, harmonisation, analysis, and interpretation of the data. The data management team undertook data collation and harmonisation. Writing committee Nadeem Sarwar* PhD, University of Cambridge, UK; Adam S Butterworth* PhD, University of Cambridge, UK; Daniel F Freitag MPhil, University of Cambridge, UK; John Gregson MPhil, University of Cambridge, UK; Peter Willeit MD, University of Cambridge, UK; Donal N Gorman MPhil, University of Cambridge, UK; Pei Gao PhD, University of Cambridge, UK; Danish Saleheen MD, University of Cambridge, UK; Augusto Rendon PhD, University of Cambridge and MRC Biostatistics Unit, UK; Christopher P Nelson PhD, University of Leicester, UK; Peter S Braund PhD, University of Leicester, UK; Alistair S Hall PhD, University of Leeds, UK; Daniel I Chasman PhD, Brigham and Women's Hospital and Harvard Medical School, USA; Anne Tybjærg-Hansen MD, Copenhagen University Hospital, University of Copenhagen, Denmark; John C Chambers PhD, Imperial College London, UK; Emelia J Benjamin MD, Boston University School of Medicine and Public Health, and National Heart, Lung, and Blood Institute's Framingham Heart Study, USA; Paul W Franks PhD, Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital, Lund University, Malmö, Sweden, Department of Nutrition, Harvard School of Public Health, Boston, MA, USA, and Department of Public Health and Clinical Medicine, Section for Medicine, Umeå University, Umeå, Sweden; Robert Clarke MD, University of Oxford, UK; Arthur A M Wilde MD, Academic Medical Center, University of Amsterdam, Netherlands; Mieke D Trip MD, Academic Medical Center, University of Amsterdam, Netherlands; Maristella Steri PhD, IRGB-CNR, Italy; Jacqueline C M Witteman PhD, Erasmus Medical Center, Netherlands; Lu Qi MD, Harvard School of Public Health, Brigham and Women's Hospital, USA; C Ellen van der Schoot MD, Sanquin Research, Netherlands; Ulf de Faire MD, Karolinska Institutet, Sweden; Jeanette Erdmann PhD, University of Lübeck, Germany; Heather M Stringham PhD, University of Michigan, Ann Arbor, USA; Wolfgang Koenig MD, University of Ulm, Germany; Daniel J Rader MD, University of Pennsylvania, USA; David Melzer PhD, Peninsula College of Medicine and Dentistry, University of Exeter, UK; David Reich PhD, Harvard Medical School, USA; Bruce M Psaty MD, University of Washington, USA; Marcus E Kleber PhD, LURIC Study nonprofit LLC, Freiburg, Germany; Demosthenes B Panagiotakos MD, Harokopio University of Athens, Greece; Johann Willeit MD, Medical University Innsbruck, Austria; Patrik Wennberg MD, Umeå University, Sweden; Mark Woodward PhD, University of Sydney, Australia; Svetlana Adamovic PhD, Sahlgrenska University Hospital, Sweden; Eric B Rimm ScD, Harvard University, USA; Tom W Meade FRS, London School of Hygiene and Tropical Medicine, UK; Richard F Gillum MD, Center for Disease Control and Prevention, USA; Jonathan A Shaffer PhD, Columbia University Medical Center, USA; Albert Hofman MD, Erasmus Medical Center, Netherlands; Altan Onat MD, Istanbul University, Turkey; Johan Sundström MD, Uppsala University, Sweden; Sylvia Wassertheil-Smoller PhD, Albert Einstein College of Medicine, USA; Dan Mellström MD, Sahlgrenska University Hospital, Sweden; John Gallacher PhD, Cardiff University, UK; Mary Cushman MD, University of Vermont, USA; Russell P Tracy PhD, University of Vermont, USA; Jussi Kauhanen MD, University of Eastern Finland, Finland; Magnus Karlsson MD, Lund University, Sweden; Jukka T Salonen MD, Metabolic Analytical Services Inc, Finland; Lars Wilhelmsen MD, University of Gothenburg, Sweden; Philippe Amouyel MD, Institut Pasteur de Lille, France; Bernard Cantin MD, Hôpital Laval, Canada; Lyle G Best MD, Missouri Breaks Industries Research Inc, Timber Lake, USA; Yoav Ben-Shlomo PhD, University of Bristol, UK; JoAnn E Manson MD, Harvard Medical School, USA; George Davey-Smith MD, University of Bristol, UK; Paul I W de Bakker PhD, Brigham and Women's Hospital, USA; Christopher J O'Donnell MD, Harvard Medical School, USA; James F Wilson DPhil, University of Edinburgh, UK; Anthony G Wilson PhD, University of Sheffield, UK; Themistocles L Assimes MD, Stanford University School of Medicine, USA; John-Olov Jansson MD, Gothenburg University, Sweden; Claes Ohlsson MD, Sahlgrenska University Hospital, Gothenburg, Sweden; Åsa Tivesten MD, Sahlgrenska University Hospital, Gothenburg, Sweden; Östen Ljunggren MD, University of Uppsala, Sweden; Muredach P Reilly MB, University of Pennsylvania, USA; Anders Hamsten FRCP, Karolinska Institutet, Stockholm, Sweden; Erik Ingelsson MD, Karolinska Institutet, Sweden; Francois Cambien MD, INSERM, France; Joseph Hung FRACP, University of Western Australia, Australia; G Neil Thomas PhD, University of Birmingham, UK; Michael Boehnke PhD, University of Michigan, USA; Heribert Schunkert MD, University of Lübeck, Germany; Folkert W Asselbergs MD, University Medical Centre Utrecht, Netherlands; John J P Kastelein MD, Academic Medical Center, University of Amsterdam, Netherlands; Vilmundur Gudnason MD, Icelandic Heart Association and University of Iceland, Iceland; Veikko Salomaa MD, National Institute for Health and Welfare, Finland; Tamara B Harris MD, US National Institute on Aging, USA; Jaspal S Kooner FRCP, National Heart and Lung Institute, Imperial College London, UK; Kristine H Allin MD, Copenhagen University Hospital, University of Copenhagen, Denmark; Børge G Nordestgaard MD, Copenhagen University Hospital, University of Copenhagen, Denmark; Jemma C Hopewell PhD, University of Oxford, UK; Alison H Goodall PhD, University of Leicester, UK; Cardiogenics Consortium; Paul M Ridker MD, Brigham and Women's Hospital and Harvard Medical School, USA; Hilma Hólm MD, deCODE genetics, Reykjavik, Iceland; Hugh Watkins FMedSci, University of Oxford, UK; Willem H Ouwehand MD, University of Cambridge, UK; Nilesh J Samani FMedSci, University of Leicester, UK; Stephen Kaptoge PhD, University of Cambridge, UK; Emanuele Di Angelantonio MD, University of Cambridge, UK; Olivier Harari PhD, Hoffmann-La Roche, Switzerland; John Danesh FRCP, University of Cambridge, UK. *Denotes equal contribution. Members of the IL6R Genetics Consortium and the Emerging Risk Factors Collaboration ADVANCE: Themistocles L Assimes, Thomas Quertermous, Alan S Go, Mark A Hlatky, Joshua W Knowles; AGES: Vilmundur Gudnason, Albert V Smith; ATTICA: Demosthenes B Panagiotakos, Christina Chrysohoou, Christos Pitsavos, Christodoulos Stefanadis; BHF-FHS: Christopher P Nelson, Peter S Braund, Nilesh J Samani, Alistair S Hall, Anthony J Balmforth, John R Thompson; BLOODOMICS: Augusto Rendon, Arthur A M Wilde, Mieke D Trip, C Ellen van der Schoot, John J P Kastelein, Willem H Ouwehand, Suthesh Sivapalaratnam, Stephani Maiwald, Hanneke Basart, Mahdi Motazacker, Jonas S S G de Jong, Lucas R C Dekker, Michael Tanck, Connie R Bezzina; BRHS: Peter H Whincup, Richard W Morris, S Goya Wannamethee; BRUN: Johann Willeit, Stefan Kiechl; CAPS: John Gallacher, John W G Yarnell, Gordon Lowe, Ann Rumley; CARDIOGENICS: Nilesh J Samani, Alison H Goodall, Francois Cambien (see appendix p 26 for acknowledgments); CHS: Mary Cushman, Kenneth J Mukamal (see http://www.chs-nhlbi.org for acknowledgments); COPEN/CIHDS: Børge G Nordestgaard, Anne Tybjærg-Hansen, Kristine H Allin; COROGENE: Veikko Salomaa, Aki S Havulinna, Marja-Liisa Lokki, Markku S Nieminen, Samuli Ripatti, Juha Sinisalo; CUDAS/CUPID: Joseph Hung, Brendan M McQuillan, John P Beilby, Peter L Thompson; DECODE: Hilma Hólm, Gu mar Thorleifsson, Gu mundur Thorgeirsson, Unnur Thorsteinsdóttir, Kari Stefansson; DILGOM: Veikko Salomaa, Antti Jula, Satu Männistö, Markus Perola, Emmi Tikkanen; EPICNL: Folkert W Asselbergs, Jolanda M A Boer, N Charlotte Onland-Moret, Yvonne T van der Schouw, W M Monique Verschuren, Paul I W de Bakker; FIA: Patrik Wennberg, Jan-Håkan Jansson; FINRISK92,97: Veikko Salomaa; FLETCHER: Mark Woodward; FRAM: Emelia J Benjamin, Josée Dupuis, João D Fontes, Xiaoyan Yin, Christopher J O'Donnell; FUSION: Michael Boehnke, Heather M Stringham, Jaakko Tuomilehto; GerMIFS1 / GerMIFS2: Heribert Schunkert, Jeanette Erdmann, Inke R Koenig, Janja Nahrstaedt, Christina Loley, Klaus Stark, Christina Willenborg, Christian Hengstenberg, Stefan Schreiber, Michael Preuss; GLACIER: Paul W Franks, Inês Barroso, Göran Hallmans, Dmitry Shungin; Guangzhou Biobank Cohort Study: G Neil Thomas, Kar Keung Cheng, Tai Hing Lam, Chao Chiang Jiang; HEALTH: David Reich, Tamara B Harris; HPFS: Eric B Rimm, Jennifer Pai; HPS: Jemma C Hopewell, Rory Collins, Sarah Parish, Jane Armitage; HUNT: Heather M Stringham, Anne Jackson, Kristian Hveem; HVHS: Bruce M Psaty, Kerri L Wiggins, Susan R Heckbert, Nicholas L Smith, Joshua C Bis; inCHIANTI: David Melzer, Luigi Ferrucci, Jack M Guralnik, Stefania Bandinelli, Andrew B Singleton; KIHD: Jussi Kauhanen, Jukka T Salonen, Tomi-Pekka Tuomainen, Sudhir Kurl; LEADER: Tom W Meade; LOLIPOP: John C Chambers, Jaspal S Kooner, Weihua Zhang, Angad S Kooner, Debashis Das; LURIC: Marcus E Kleber, Winfried März, Hubert Scharnagl, Bernhard O Böhm, Bernhard R Winkelmann; MESA: Mary Cushman, Russell P Tracy, Aaron R Folsom, Bruce M Psaty, Steven J Shea (see http://www.mesa-nhlbi.org for acknowledgments); METSIM: Heather M Stringham, Markku Laakso, Johanna Kuusisto; MOGERAUG: Wolfgang Koenig, Jens Baumert, Barbara Thorand, Thomas Illig, Christa Meisinger; MOSWEGOT: Lars Wilhelmsen, Annika Rosengren; MrOS: John-Olov Jansson, Svetlana Adamovic, Magnus K Karlsson, Östen Ljunggren, Dan Mellström, Claes Ohlsson, Åsa Tivesten; NHANESIII: Richard F Gillum; NHS: Eric B Rimm, JoAnn E Manson, Lu Qi, Frank B Hu, Susan E Hankinson; NSHS: Jonathan A Shaffer, Karina W Davidson; ORCADES: James F Wilson, Ross Fraser, Sarah Wild, Harry Campbell; PENNCATH: Daniel J Rader, Muredach P Reilly, Atif Qasim, Liming Qu, Mingyao Li; PIVUS: Erik Ingelsson, Lars Lind, Johan Sundström, Ann-Christine Syvänen; PRIME: Philippe Amouyel, Dominique Arveiler; PROCARDIS: Robert Clarke, Hugh Watkins, Martin Farrall, Jemma C Hopewell, John F Peden; PROMIS: Danish Saleheen, Panos Deloukas, Nasir Sheikh, Asif Rasheed, John Danesh; QUEBEC: Bernard Cantin, Gilles R Dagenais; ROTT: Jacqueline C M Witteman, Albert Hofman, Abbas Dehghan, Cornelia M van Duijn, Andre G Uitterlinden; SARDINIA: Maristella Steri, Goncalo R Abecasis, Francesco Cucca, Serena Sanna, Manuela Uda, David Schlessinger; SCARF: Anders Hamsten, Maria Sabater-Lleal, Angela Silveira; SHEEP: Ulf de Faire, Bruna Gigante; SHS: Lyle G Best, Barbara V Howard; SPEED: George Davey-Smith, Yoav Ben-Shlomo; TARFS: Altan Onat; ULSAM: Erik Ingelsson, Johan Sundström, Lars Lind, Samar Basu, Ann-Christine Syvänen; WGHS: Paul M Ridker, Daniel I Chasman, Lynda M Rose; WHI-HaBPS: Sylvia Wassertheil-Smoller; WHS: Paul M Ridker, Julie Buring. Data management team Matthew Walker, Sarah Watson. Coordinating centre Adam S Butterworth, Emanuele Di Angelantonio, Daniel F Freitag, Pei Gao, Donal N Gorman, John Gregson, Stephen Kaptoge, Lisa Pennells, Nadeem Sarwar, Danish Saleheen, Simon G Thompson, Matthew Walker, Sarah Watson, Peter Willeit, Angela M Wood, David Wormser, John Danesh (principal investigator). Conflicts of interest Since April, 2011, Nadeem Sarwar has been a full-time employee of Pfizer Inc. Olivier Harari is an employee of Roche Products. Hilma Holm is an employee of deCODE genetics. Bruce Psaty serves on a data safety and monitoring board for a clinical trial of a device funded by the manufacturer Zoll. JoAnn Manson is listed as a co-inventor on a pending patent held by Brigham and Women's Hospital, Harvard Medical School, that relates to inflammatory markers in diabetes prediction. Paul M Ridker is listed as a co-inventor on patents held by Brigham and Women's Hospital that relate to the use of inflammatory markers in cardiovascular disease, and that have been licensed to AstraZeneca and Siemens. John Danesh has received research funding from the British Heart Foundation, BUPA Foundation, Denka, diaDexus, European Union, European Research Council, Evelyn Trust, Fogarty International Centre, GlaxoSmithKline, Medical Research Council, Merck Sharp and Dohme, National Heart, Lung and Blood Institute, National Institute of Neurological Disorders and Stroke, National Institute for Health Research, Novartis, Pfizer, Roche, Wellcome Trust, and UK Biobank, and has served on advisory boards for Merck, Pfizer, and Novartis, for which he has received compensation. All other members of the writing committee declare that they have no conflicts of interest. Acknowledgments The coordinating centre was supported by the British Heart Foundation ( RG/08/014 ), the UK Medical Research Council, the UK National Institute of Health Research, Cambridge Biomedical Research Centre, and a specific grant from the BUPA Foundation. Various sources have supported recruitment, follow-up, and laboratory measurements in the studies contributing to this report. Investigators of several of these studies have contributed to a list naming some of these funding sources . Sekar Kathiresan, Kenneth G C Smith, and John Todd commented helpfully on an earlier version of this report.

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Cite this

Sarwar, N., Butterworth, A. S., Freitag, D. F., Gregson, J., Willeit, P., Gorman, D. N., Gao, P., Saleheen, D., Rendon, A., Nelson, C. P., Braund, P. S., Hall, A. S., Chasman, D. I., Tybjærg-Hansen, A., Chambers, J. C., Benjamin, E. J., Franks, P. W., Clarke, R., Wilde, A. A., ... Preuss, M. (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

@article{1885159e56d742959cc213213fc795b8,

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 = "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 H. Schunkert and Christina Willenborg and \{Members of the IL6R Genetics Consortium and the Emerging Risk Factors Collaboration\} and Michael Preuss",

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

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pages = "1205--1213",

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Sarwar, N, Butterworth, AS, Freitag, DF, Gregson, J, Willeit, P, Gorman, DN, Gao, P, Saleheen, D, Rendon, A, Nelson, CP, Braund, PS, Hall, AS, Chasman, DI, Tybjærg-Hansen, A, Chambers, JC, Benjamin, EJ, Franks, PW, Clarke, R, Wilde, AA, Trip, MD, Steri, M, Witteman, JC, Qi, L, van der Schoot, CE, de Faire, U, Erdmann, J, Stringham, HM, Koenig, W, Rader, DJ, Melzer, D, Reich, D, Psaty, BM, Kleber, ME, Panagiotakos, DB, Willeit, J, Wennberg, P, Woodward, M, Adamovic, S, Rimm, EB, Meade, TW, Gillum, RF, Shaffer, JA, Hofman, A, Onat, A, Sundström, J, Wassertheil-Smoller, S, Mellström, D, Schunkert, H, Willenborg, C, Members of the IL6R Genetics Consortium and the Emerging Risk Factors Collaboration & Preuss, M 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

TY - JOUR

T1 - Interleukin-6 receptor pathways in coronary heart disease: A collaborative meta-analysis of 82 studies

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 - Schunkert, H.

AU - Willenborg, Christina

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

AU - Preuss, Michael

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 - https://www.scopus.com/pages/publications/84859210770

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

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

M3 - Journal articles

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

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UN SDGs

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