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

作者：D. Swerdlow, M. Holmes, K. Kuchenbaecker, J. Engmann, T. Shah, R. Sofat, Yiran Guo, C. Chung, A. Peasey, R. Pfister, S. Mooijaart, H. Ireland, M. Leusink, C. Langenberg, Kawah Li, J. Palmen, Philip N. Howard, J. Cooper, F. Drenos, J. Hardy, M. Nalls, Y. Li, G. Lowe, Marlene C. W. Stewart, S. Bielinski, J. Peto, N. Timpson, J. Gallacher, M. Dunlop, R. Houlston, I. Tomlinson, I. Tzoulaki, J. Luan, J. Boer, N. Forouhi, N. Onland-Moret, Y. T. van der Schouw, R. Schnabel, J. Hubacek, R. Kubínová, M. Baceviciene, A. Tamošiūnas, A. Pająk, R. Topor-Madry, S. Malyutina, D. Baldassarre, B. Sennblad, E. Tremoli, U. de Faire, L. Ferrucci, Stefania Bandenelli, Toshiko Tanaka, J. Meschia, A. Singleton, G. Navis, Irene Mateo Leach, S. Bakker, R. Gansevoort, I. Ford, S. Epstein, M. Burnett, J. Devaney, J. Jukema, R. Westendorp, Gert Jan de Borst, Y. van der Graaf, P. D. de Jong, A. Mailand-van der Zee, O. Klungel, A. de Boer, P. Doevendans, J. Stephens, C. Eaton, Jennifer G. Robinson, J. Manson, F. Fowkes, Timonthy M Frayling, J. Price, P. Whincup, R. Morris, D. Lawlor, G. Smith, Y. Ben-Shlomo, S. Redline, L. Lange, M. Kumari, N. Wareham, W. Verschuren, E. Benjamin, J. Whittaker, A. Hamsten, F. Dudbridge, J. Delaney, A. Wong, D. Kuh, R. Hardy, B. A. Castillo, John J. Connolly, P. van der Harst, E. Brunner, M. Marmot, C. Wassel, S. Humphries, P. Talmud, M. Kivimaki, F. Asselbergs, M. Voevoda, M. Bobák, H. Pikhart, James G. Wilson, H. Hakonarson, A. Reiner, B. Keating, N. Sattar, A. Hingorani, J. Casas · 发表于：The Lancet · 年份：2012 · DOI：10.1016/S0140-6736(12)60110-X · 被引用次数：1021 · 研究领域：Medicine

Summary 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 coronar...