The interleukin-6 receptor as a target for prevention of coronary heart disease: A mendelian randomisation analysis
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 K., 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 R., 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., Leach IM., Bakker SJL., Gansevoort RT., Ford I., Epstein SE., Burnett MS., Devaney JM., Jukema JW., Westendorp RGJ., De Borst GJ., Van Der Graaf Y., De Jong PA., Maitland-Van Der Zee AH., Klungel OH., De Boer A., Doevendans PA., Stephens JW., Eaton CB., Robinson JG., Manson JE., Fowkes FGR., Frayling TM., Price J., 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.
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.