TY - JOUR
T1 - The interleukin-6 receptor as a target for prevention of coronary heart disease
T2 - A mendelian randomisation analysis
AU - The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium
AU - Swerdlow, Daniel I.
AU - Holmes, Michael V.
AU - Kuchenbaecker, Karoline B.
AU - Engmann, Jorgen E.L.
AU - Shah, Tina
AU - Sofat, Reecha
AU - Guo, Yiran
AU - Chung, Christina
AU - Peasey, Anne
AU - Pfister, Roman
AU - Mooijaart, Simon P.
AU - Ireland, Helen A.
AU - Leusink, Maarten
AU - Langenberg, Claudia
AU - Li, Kawah
AU - Palmen, Jutta
AU - Howard, Philip
AU - Cooper, Jackie A.
AU - Drenos, Fotios
AU - Hardy, John
AU - Nalls, Michael A.
AU - Li, Yun Rose
AU - Lowe, Gordon
AU - Stewart, Marlene
AU - Bielinski, Suzette J.
AU - Peto, Julian
AU - Timpson, Nicholas J.
AU - Gallacher, John
AU - Dunlop, Malcolm
AU - Houlston, Richard
AU - Tomlinson, Ian
AU - Tzoulaki, Ioanna
AU - Luan, Jian'An
AU - Boer, Jolanda M.A.
AU - Forouhi, Nita G.
AU - Onland-Moret, N. Charlotte
AU - Van Der Schouw, Yvonne T.
AU - Schnabel, Renate
AU - Hubacek, Jaroslav A.
AU - Kubinova, Ruzena
AU - Baceviciene, Migle
AU - Tamosiunas, Abdonas
AU - Pajak, Andrzej
AU - Topor-Madry, Roman
AU - Malyutina, Sofia
AU - Baldassarre, Damiano
AU - Sennblad, Bengt
AU - Tremoli, Elena
AU - De Faire, Ulf
AU - Meschia, James F.
PY - 2012/3/1
Y1 - 2012/3/1
N2 - 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.
AB - 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.
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U2 - 10.1016/S0140-6736(12)60110-X
DO - 10.1016/S0140-6736(12)60110-X
M3 - Article
C2 - 22421340
AN - SCOPUS:84859215358
SN - 0140-6736
VL - 379
SP - 1214
EP - 1224
JO - The Lancet
JF - The Lancet
IS - 9822
ER -