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, Daniel I Swerdlow, Michael V Holmes, Karoline B Kuchenbaecker, Jorgen E L Engmann, Tina Shah, Reecha Sofat, Yiran Guo, Christina Chung, Anne Peasey, Roman Pfister, Simon P Mooijaart, Helen A Ireland, Maarten Leusink, Claudia Langenberg, Ka Wah Li, Jutta Palmen, Philip Howard, Jackie A Cooper, Fotios Drenos, John Hardy, Michael A Nalls, Yun Rose Li, Gordon Lowe, Marlene Stewart, Suzette J Bielinski, Julian Peto, Nicholas J Timpson, John Gallacher, Malcolm Dunlop, Richard Houlston, Ian Tomlinson, Ioanna Tzoulaki, Jian'an Luan, Jolanda M A Boer, Nita G Forouhi, N Charlotte Onland-Moret, Yvonne T van der Schouw, Renate B Schnabel, Jaroslav A Hubacek, Ruzena Kubinova, Migle Baceviciene, Abdonas Tamosiunas, Andrzej Pajak, Roman Topor-Madry, Sofia Malyutina, Damiano Baldassarre, Bengt Sennblad, Elena Tremoli, Ulf de Faire, Luigi Ferrucci, Stefania Bandenelli, Toshiko Tanaka, James F Meschia, Andrew Singleton, Gerjan Navis, Irene Mateo Leach, Stephan J L Bakker, Ron T Gansevoort, Ian Ford, Stephen E Epstein, Mary Susan Burnett, Joe M Devaney, J Wouter Jukema, Rudi G J Westendorp, Gert Jan de Borst, Yolanda van der Graaf, Pim A de Jong, Anke-Hilse Mailand-van der Zee, Olaf H Klungel, Anthonius de Boer, Pieter A Doevendans, Jeffrey W Stephens, Charles B Eaton, Jennifer G Robinson, JoAnn E Manson, F Gerry Fowkes, Timonthy M Frayling, Jackie F Price, Peter H Whincup, Richard W Morris, Debbie A Lawlor, George Davey Smith, Yoav Ben-Shlomo, Susan Redline, Leslie A Lange, Meena Kumari, Nick J Wareham, W M Monique Verschuren, Emelia J Benjamin, John C Whittaker, Anders Hamsten, Frank Dudbridge, J A Chris Delaney, Andrew Wong, Diana Kuh, Rebecca Hardy, Berta Almoguera Castillo, John J Connolly, Pim van der Harst, Eric J Brunner, Michael G Marmot, Christina L Wassel, Steve E Humphries, Philippa J Talmud, Mika Kivimaki, Folkert W Asselbergs, Mikhail Voevoda, Martin Bobak, Hynek Pikhart, James G Wilson, Hakon Hakonarson, Alex P Reiner, Brendan J Keating, Naveed Sattar, Aroon D Hingorani, Juan Pablo Casas, Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium, Daniel I Swerdlow, Michael V Holmes, Karoline B Kuchenbaecker, Jorgen E L Engmann, Tina Shah, Reecha Sofat, Yiran Guo, Christina Chung, Anne Peasey, Roman Pfister, Simon P Mooijaart, Helen A Ireland, Maarten Leusink, Claudia Langenberg, Ka Wah Li, Jutta Palmen, Philip Howard, Jackie A Cooper, Fotios Drenos, John Hardy, Michael A Nalls, Yun Rose Li, Gordon Lowe, Marlene Stewart, Suzette J Bielinski, Julian Peto, Nicholas J Timpson, John Gallacher, Malcolm Dunlop, Richard Houlston, Ian Tomlinson, Ioanna Tzoulaki, Jian'an Luan, Jolanda M A Boer, Nita G Forouhi, N Charlotte Onland-Moret, Yvonne T van der Schouw, Renate B Schnabel, Jaroslav A Hubacek, Ruzena Kubinova, Migle Baceviciene, Abdonas Tamosiunas, Andrzej Pajak, Roman Topor-Madry, Sofia Malyutina, Damiano Baldassarre, Bengt Sennblad, Elena Tremoli, Ulf de Faire, Luigi Ferrucci, Stefania Bandenelli, Toshiko Tanaka, James F Meschia, Andrew Singleton, Gerjan Navis, Irene Mateo Leach, Stephan J L Bakker, Ron T Gansevoort, Ian Ford, Stephen E Epstein, Mary Susan Burnett, Joe M Devaney, J Wouter Jukema, Rudi G J Westendorp, Gert Jan de Borst, Yolanda van der Graaf, Pim A de Jong, Anke-Hilse Mailand-van der Zee, Olaf H Klungel, Anthonius de Boer, Pieter A Doevendans, Jeffrey W Stephens, Charles B Eaton, Jennifer G Robinson, JoAnn E Manson, F Gerry Fowkes, Timonthy M Frayling, Jackie F Price, Peter H Whincup, Richard W Morris, Debbie A Lawlor, George Davey Smith, Yoav Ben-Shlomo, Susan Redline, Leslie A Lange, Meena Kumari, Nick J Wareham, W M Monique Verschuren, Emelia J Benjamin, John C Whittaker, Anders Hamsten, Frank Dudbridge, J A Chris Delaney, Andrew Wong, Diana Kuh, Rebecca Hardy, Berta Almoguera Castillo, John J Connolly, Pim van der Harst, Eric J Brunner, Michael G Marmot, Christina L Wassel, Steve E Humphries, Philippa J Talmud, Mika Kivimaki, Folkert W Asselbergs, Mikhail Voevoda, Martin Bobak, Hynek Pikhart, James G Wilson, Hakon Hakonarson, Alex P Reiner, Brendan J Keating, Naveed Sattar, Aroon D Hingorani, Juan Pablo Casas

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 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.

Trial registration: ClinicalTrials.gov NCT00000611.

Copyright © 2012 Elsevier Ltd. All rights reserved.

Figures

Figure 1
Figure 1
Association of the IL6R rs7529229 variant with (A) interleukin 6, (B) C-reactive protein, and (C) fibrinogen concentration Estimates are based on pairwise comparison of individuals heterozygous or homozygous for the variant T allele with reference to the CC homozygous group. The total number of studies and participants are also shown. Error bars show 95% CIs.
Figure 2
Figure 2
Associations of the minor allele of the IL6R SNP rs7529229 and tocilizumab (8 mg/kg) versus placebo with commonly reported biomarkers Concordance between the drug and genetic variants is shown. Effects are presented as standardised mean difference apart from loge transformed variables (shown by *), for which rs7529229 effects represent the mean difference on the log scale. Estimates for soluble interleukin-6 receptor were not plotted since their substantially greater magnitude would disrupt the scale of the graph: standardised mean differences were 0·75 (95% CI 0·59–0·91) ng/mL per minor allele for rs7529229, and 93·67 (95% CI 90·27–97·06) ng/mL for tocilizumab 8 mg/kg versus placebo. SNP=single nucleotide polymorphism.
Figure 3
Figure 3
Association of IL6R rs7529229 with risk of fatal and non-fatal coronary heart disease Individual study odds ratios were based on a per-allele model and pooled with fixed effects meta-analysis. *Data published in reference 30. †Data published in reference 32.
Figure 4
Figure 4
Association of IL6R rs7529229 with secondary and safety endpoints Summary per-allele odds ratio for cardiovascular and non-cardiovascular endpoints for the IL6R rs7529229 variant. Individual study odds ratios were based on a per-allele model in the present collaborative analysis and genome-wide association studies and pooled with fixed effects meta-analysis. CHD=coronary heart disease. CVD=cardiovascular disease.

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