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 inflammation. 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 efficacy and safety of IL6R inhibition for primary prevention of coronary heart disease. We compared genetic findings with the effects 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 fibrinogen concentrations (decrease per allele 0·85%, 95% CI 0·60-1·10). This pattern of effects 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 populations 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. FUNDING: UK Medical Research Council; British Heart Foundation; Rosetrees Trust; US National Heart, Lung, and Blood Institute; Du Pont Pharma; Chest, Heart and Stroke Scotland; Wellcome Trust; Coronary Thrombosis Trust; Northwick Park Institute for Medical Research; UCLH/UCL Comprehensive Medical Research Centre; US National Institute on Aging; Academy of Finland; Netherlands Organisation for Health Research and Development; SANCO; Dutch Ministry of Public Health, Welfare and Sports; World Cancer Research Fund; Agentschap NL; European Commission; Swedish Heart-Lung Foundation; Swedish Research Council; Strategic Cardiovascular Programme of the Karolinska Institutet; Stockholm County Council; US National Institute of Neurological Disorders and Stroke; MedStar Health Research Institute; GlaxoSmithKline; Dutch Kidney Foundation; US National Institutes of Health; Netherlands Interuniversity Cardiology Institute of the Netherlands; Diabetes UK; European Union Seventh Framework Programme; National Institute for Healthy Ageing; Cancer Research UK; MacArthur Foundation.
The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis / D.I. Swerdlow, M.V. Holmes, K.B. Kuchenbaecker, J.E. Engmann, T. Shah, R. Sofat, Y. Guo, C. Chung, A. Peasey, R. Pfister, S.P. Mooijaart, H.A. Ireland, M. Leusink, C. Langenberg, K. Li, J. Palmen, P. Howard, J.A. Cooper, F. Drenos, J. Hardy, M.A. Nalls, Y.R. Li, G. Lowe, M. Stewart, S.J. Bielinski, J. Peto, N.J. Timpson, J. Gallacher, M. Dunlop, R. Houlston, I. Tomlinson, I. Tzoulaki, J. Luan, J.M. Boer, N.G. Forouhi, N.C. Onland-Moret, Y.T. van der Schouw, R.B. Schnabel, J.A. Hubacek, R. Kubinova, M. Baceviciene, A. Tamosiunas, A. Pajak, R. Topor-Madry, S. Malyutina, D. Baldassarre, B. Sennblad, E. Tremoli, U. de Faire, L. Ferrucci, S. Bandenelli, T. Tanaka, J.F. Meschia, A. Singleton, G. Navis, I. Mateo Leach, S.J. Bakker, R.T. Gansevoort, I. Ford, S.E. Epstein, M.S. Burnett, J.M. Devaney, J.W. Jukema, R.G. Westendorp, G.J. de Borst, Y. van der Graaf, P.A. de Jong, A.H. Maitland-van der Zee, O.H. Klungel, A. de Boer, P.A. Doevendans, J.W. Stephens, C.B. Eaton, J.G. Robinson, J.E. Manson, F.G. Fowkes, T.M. Frayling, J.F. Price, P.H. Whincup, R.W. Morris, D.A. Lawlor, G.D. Smith, Y. Ben-Shlomo, S. Redline, L.A. Lange, M. Kumari, N.J. Wareham, W.M. Verschuren, E.J. Benjamin, J.C. Whittaker, A. Hamsten, F. Dudbridge, J.A. Delaney, A. Wong, D. Kuh, R. Hardy, B.A. Castillo, J.J. Connolly, P. van der Harst, E.J. Brunner, M.G. Marmot, C.L. Wassel, S.E. Humphries, P.J. Talmud, M. Kivimaki, F.W. Asselbergs, M. Voevoda, M. Bobak, H. Pikhart, J.G. Wilson, H. Hakonarson, A.P. Reiner, B.J. Keating, N. Sattar. - In: THE LANCET. - ISSN 0140-6736. - 379:9822(2012 Mar 31), pp. 1214-1224. [10.1016/S0140-6736(12)60110-X]
The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis
D. Baldassarre;E. Tremoli;
2012
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 inflammation. 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 efficacy and safety of IL6R inhibition for primary prevention of coronary heart disease. We compared genetic findings with the effects 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 fibrinogen concentrations (decrease per allele 0·85%, 95% CI 0·60-1·10). This pattern of effects 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 populations 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. FUNDING: UK Medical Research Council; British Heart Foundation; Rosetrees Trust; US National Heart, Lung, and Blood Institute; Du Pont Pharma; Chest, Heart and Stroke Scotland; Wellcome Trust; Coronary Thrombosis Trust; Northwick Park Institute for Medical Research; UCLH/UCL Comprehensive Medical Research Centre; US National Institute on Aging; Academy of Finland; Netherlands Organisation for Health Research and Development; SANCO; Dutch Ministry of Public Health, Welfare and Sports; World Cancer Research Fund; Agentschap NL; European Commission; Swedish Heart-Lung Foundation; Swedish Research Council; Strategic Cardiovascular Programme of the Karolinska Institutet; Stockholm County Council; US National Institute of Neurological Disorders and Stroke; MedStar Health Research Institute; GlaxoSmithKline; Dutch Kidney Foundation; US National Institutes of Health; Netherlands Interuniversity Cardiology Institute of the Netherlands; Diabetes UK; European Union Seventh Framework Programme; National Institute for Healthy Ageing; Cancer Research UK; MacArthur Foundation.
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