The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis.
Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium None., Swerdlow DI., Holmes MV., Kuchenbaecker KB., Engmann JEL., Shah T., Sofat R., Guo Y., Chung C., Peasey A., Pfister R., Mooijaart SP., Ireland HA., Leusink M., Langenberg C., Li KW., Palmen J., Howard P., Cooper JA., Drenos F., Hardy J., Nalls MA., Li YR., Lowe G., Stewart M., Bielinski SJ., Peto J., Timpson NJ., Gallacher J., Dunlop M., Houlston R., Tomlinson I., Tzoulaki I., Luan J., Boer JMA., Forouhi NG., Onland-Moret NC., van der Schouw YT., Schnabel RB., Hubacek JA., Kubinova R., Baceviciene M., Tamosiunas A., Pajak A., Topor-Madry R., Malyutina S., Baldassarre D., Sennblad B., Tremoli E., de Faire U., Ferrucci L., Bandenelli S., Tanaka T., Meschia JF., Singleton A., Navis G., Mateo Leach I., Bakker SJL., Gansevoort RT., Ford I., Epstein SE., Burnett MS., Devaney JM., Jukema JW., Westendorp RGJ., Jan de Borst G., van der Graaf Y., de Jong PA., Mailand-van der Zee A-H., Klungel OH., de Boer A., Doevendans PA., Stephens JW., Eaton CB., Robinson JG., Manson JE., Fowkes FG., Frayling TM., Price JF., Whincup PH., Morris RW., Lawlor DA., Smith GD., Ben-Shlomo Y., Redline S., Lange LA., Kumari M., Wareham NJ., Verschuren WMM., Benjamin EJ., Whittaker JC., Hamsten A., Dudbridge F., Delaney JAC., Wong A., Kuh D., Hardy R., Castillo BA., Connolly JJ., van der Harst P., Brunner EJ., Marmot MG., Wassel CL., Humphries SE., Talmud PJ., Kivimaki M., Asselbergs FW., Voevoda M., Bobak M., Pikhart H., Wilson JG., Hakonarson H., Reiner AP., Keating BJ., Sattar N., Hingorani AD., Casas JP.
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.