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

The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium

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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 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.

Original languageEnglish (US)
Pages (from-to)1214-1224
Number of pages11
JournalThe Lancet
Volume379
Issue number9822
DOIs
StatePublished - Mar 1 2012

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Mendelian Randomization Analysis
Interleukin-6 Receptors
Coronary Disease
Alleles
Single Nucleotide Polymorphism
Rheumatoid Arthritis
Interleukin-6
Therapeutic Uses
Primary Prevention
Random Allocation
C-Reactive Protein

ASJC Scopus subject areas

  • Medicine(all)

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The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium (2012). The interleukin-6 receptor as a target for prevention of coronary heart disease: A mendelian randomisation analysis. The Lancet, 379(9822), 1214-1224. https://doi.org/10.1016/S0140-6736(12)60110-X

The interleukin-6 receptor as a target for prevention of coronary heart disease : A mendelian randomisation analysis. / The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium.

In: The Lancet, Vol. 379, No. 9822, 01.03.2012, p. 1214-1224.

Research output: Contribution to journalArticle

The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium 2012, 'The interleukin-6 receptor as a target for prevention of coronary heart disease: A mendelian randomisation analysis', The Lancet, vol. 379, no. 9822, pp. 1214-1224. https://doi.org/10.1016/S0140-6736(12)60110-X
The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium. The interleukin-6 receptor as a target for prevention of coronary heart disease: A mendelian randomisation analysis. The Lancet. 2012 Mar 1;379(9822):1214-1224. https://doi.org/10.1016/S0140-6736(12)60110-X
The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium. / The interleukin-6 receptor as a target for prevention of coronary heart disease : A mendelian randomisation analysis. In: The Lancet. 2012 ; Vol. 379, No. 9822. pp. 1214-1224.
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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 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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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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