The interleukin-6 receptor as a target for prevention of coronary heart disease: A mendelian randomisation analysis

Daniel I. Swerdlow, Michael V. Holmes, Karoline B. Kuchenbaecker, Jorgen E L Engmann, Tina Shah, Reecha Sofat, Yiran Guo, Christina Chung, Anne Peasey, Roman Pfister, Simon P. Mooijaart, Helen A. Ireland, Maarten Leusink, Claudia Langenberg, Kawah Li, Jutta Palmen, Philip Howard, Jackie A. Cooper, Fotios Drenos, John HardyMichael A. Nalls, Yun Rose Li, Gordon Lowe, Marlene Stewart, Suzette J. Bielinski, Julian Peto, Nicholas J. Timpson, John Gallacher, Malcolm Dunlop, Richard Houlston, Ian Tomlinson, Ioanna Tzoulaki, Jian'An Luan, Jolanda M A Boer, Nita G. Forouhi, N. Charlotte Onland-Moret, Yvonne T. Van Der Schouw, Renate Schnabel, Jaroslav A. Hubacek, Ruzena Kubinova, Migle Baceviciene, Abdonas Tamosiunas, Andrzej Pajak, Roman Topor-Madry, Sofia Malyutina, Damiano Baldassarre, Bengt Sennblad, Elena Tremoli, Ulf De Faire, Luigi Ferrucci, Stefania Bandenelli, Toshiko Tanaka, James F. Meschia, Andrew Singleton, Gerjan Navis, Irene Mateo Leach, Stephan J L Bakker, Ron T. Gansevoort, Ian Ford, Stephen E. Epstein, Mary Susan Burnett, Joe M. Devaney, J. Wouter Jukema, Rudi G J Westendorp, Gert Jan De Borst, Yolanda Van Der Graaf, Pim A. De Jong, Anke Hilse Maitland-Van Der Zee, Olaf H. Klungel, Anthonius De Boer, Pieter A. Doevendans, Jeffrey W. Stephens, Charles B. Eaton, Jennifer G. Robinson, Joann E. Manson, F. Gerry R Fowkes, Timothy M. Frayling, Jackie Price, Peter H. Whincup, Richard W. Morris, Debbie A. Lawlor, George Davey Smith, Yoav Ben-Shlomo, Susan Redline, Leslie A. Lange, Meena Kumari, Nick J. Wareham, W. M Monique Verschuren, Emelia J. Benjamin, John C. Whittaker, Anders Hamsten, Frank Dudbridge, J. A Chris Delaney, Andrew Wong, Diana Kuh, Rebecca Hardy, Berta Almoguera Castillo, John J. Connolly, Pim Van Der Harst, Eric J. Brunner, Michael G. Marmot, Christina L. Wassel, Steve E. Humphries, Philippa J. Talmud, Mika Kivimaki, Folkert W. Asselbergs, Mikhail Voevoda, Martin Bobak, Hynek Pikhart, James G. Wilson, Hakon Hakonarson, Alex P. Reiner, Brendan J. Keating, Naveed Sattar, Aroon D. Hingorani, Juan Pablo Casas

Research output: Contribution to journalArticle

Abstract

Background A high circulating concentration of interleukin 6 is associated with increased risk of coronary heart disease. Blockade of the interleukin-6 receptor (IL6R) with a monoclonal antibody (tocilizumab) licensed for treatment of rheumatoid arthritis reduces systemic and articular infl ammation. However, whether IL6R blockade also reduces risk of coronary heart disease is unknown. Methods Applying the mendelian randomisation principle, we used single nucleotide polymorphisms (SNPs) in the gene IL6R to evaluate the likely effi cacy and safety of IL6R inhibition for primary prevention of coronary heart disease. We compared genetic fi ndings with the eff ects of tocilizumab reported in randomised trials in patients with rheumatoid arthritis. Findings In 40 studies including up to 133 449 individuals, an IL6R SNP (rs7529229) marking a non-synonymous IL6R variant (rs8192284; p.Asp358Ala) was associated with increased circulating log interleukin-6 concentration (increase per allele 9·45%, 95% CI 8·34-10·57) as well as reduced C-reactive protein (decrease per allele 8·35%, 95% CI 7·31-9·38) and fi brinogen concentrations (decrease per allele 0·85%, 95% CI 0·60-1·10). This pattern of eff ects was consistent with IL6R blockade from infusions of tocilizumab (4-8 mg/kg every 4 weeks) in patients with rheumatoid arthritis studied in randomised trials. In 25 458 coronary heart disease cases and 100 740 controls, the IL6R rs7529229 SNP was associated with a decreased odds of coronary heart disease events (per allele odds ratio 0·95, 95% CI 0·93-0·97, p=1·53×10-5). Interpretation On the basis of genetic evidence in human beings, IL6R signalling seems to have a causal role in development of coronary heart disease. IL6R blockade could provide a novel therapeutic approach to prevention of coronary heart disease that warrants testing in suitably powered randomised trials. Genetic studies in popu lations could be used more widely to help to validate and prioritise novel drug targets or to repurpose existing agents and targets for new therapeutic uses.

Original languageEnglish (US)
Pages (from-to)1214-1224
Number of pages11
JournalThe Lancet
Volume379
Issue number9822
DOIs
StatePublished - Mar 1 2012
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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    Swerdlow, D. I., Holmes, M. V., Kuchenbaecker, K. B., Engmann, J. E. L., Shah, T., Sofat, R., Guo, Y., Chung, C., Peasey, A., Pfister, R., Mooijaart, S. P., Ireland, H. A., Leusink, M., Langenberg, C., Li, K., Palmen, J., Howard, P., Cooper, J. A., Drenos, F., ... Casas, J. P. (2012). The interleukin-6 receptor as a target for prevention of coronary heart disease: A mendelian randomisation analysis. The Lancet, 379(9822), 1214-1224. https://doi.org/10.1016/S0140-6736(12)60110-X