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

Daniel I Swerdlow; Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium; 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; 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; 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; 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; Yun Rose Li; Andrew Wong; Jeffrey W Stephens

doi:10.1016/S0140-6736(12)60110-X

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

Journal article

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Peer reviewed

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

Daniel I Swerdlow, Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium, Michael V Holmes, Karoline B Kuchenbaecker, Jorgen E L Engmann, Tina Shah, Reecha Sofat, Yiran Guo, Christina Chung, Anne Peasey, …

The Lancet (British edition), Vol.379(9822), pp.1214-1224

03/31/2012

DOI: 10.1016/S0140-6736(12)60110-X

PMCID: PMC3316968

PMID: 22421340

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Abstract

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. 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. 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)). 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. 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.

Phenotype

Antibodies, Monoclonal, Humanized - adverse effects

Gene Frequency - genetics

Antibodies, Monoclonal, Humanized - therapeutic use

Genetic Association Studies

Receptors, Interleukin-6 - genetics

Humans

Inflammation Mediators - blood

Genotype

Treatment Outcome

Receptors, Interleukin-6 - antagonists & inhibitors

Signal Transduction - genetics

Randomized Controlled Trials as Topic

Coronary Disease - prevention & control

Coronary Disease - genetics

Signal Transduction - drug effects

Mendelian Randomization Analysis

Polymorphism, Single Nucleotide - genetics

Genetic Variation - genetics

Details

Title: Subtitle: The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis
Creators: Daniel I Swerdlow
Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium
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
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
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
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
Yun Rose Li
Andrew Wong
Jeffrey W Stephens
Resource Type: Journal article
Publication Details: The Lancet (British edition), Vol.379(9822), pp.1214-1224
DOI: 10.1016/S0140-6736(12)60110-X
PMID: 22421340
PMCID: PMC3316968
NLM abbreviation: Lancet
ISSN: 1474-547X
eISSN: 1474-547X
Publisher: England
Grant note: R01 HL036310 / NHLBI NIH HHS N01HC95169 / NHLBI NIH HHS Department of Health HHSN268200625226C / PHS HHS N01HC-95169 / NHLBI NIH HHS G1000718 / Medical Research Council PG/07/133/24260 / British Heart Foundation R01 NS039987 / NINDS NIH HHS R01 AG013196 / NIA NIH HHS 090532 / Wellcome Trust RG08/008 / British Heart Foundation RG/08/008/25291 / British Heart Foundation N01HC95163 / NHLBI NIH HHS N01HC-95162 / NHLBI NIH HHS N01HC-95165 / NHLBI NIH HHS N01HC95166 / NHLBI NIH HHS Z01 AG000015 / Intramural NIH HHS FS 05/125 / British Heart Foundation G0500877 / Medical Research Council MC_U127527198 / Medical Research Council 064947/Z/01/Z / Wellcome Trust R01 AG023522 / NIA NIH HHS 12076 / Cancer Research UK C150/A5660 / Cancer Research UK G0701075 / Medical Research Council G0802432 / Medical Research Council G0100222 / Medical Research Council NHLBI 33014 / PHS HHS HS06516 / AHRQ HHS 5215810-55000000041 / PHS HHS N01 HC095159 / NHLBI NIH HHS U01 HG005152 / NHGRI NIH HHS N01HC65226 / NHLBI NIH HHS AG13196 / NIA NIH HHS HHSN268200960009C / PHS HHS N01HC-95167 / NHLBI NIH HHS N01HC95168 / NHLBI NIH HHS N01HC95165 / NHLBI NIH HHS N01HC95162 / NHLBI NIH HHS N01HC-95161 / NHLBI NIH HHS RG/10/12/28456 / British Heart Foundation N01HC-95164 / NHLBI NIH HHS HL36310 / NHLBI NIH HHS N01HC95161 / NHLBI NIH HHS R01 NS39987 / NINDS NIH HHS U01HG005152 / NHGRI NIH HHS C1298/A8362 / Cancer Research UK G0902037 / Medical Research Council N01HC95164 / NHLBI NIH HHS N01HC95167 / NHLBI NIH HHS RR-024156 / NCRR NIH HHS F30 AR066486 / NIAMS NIH HHS FS/07/011 / British Heart Foundation 1R01 AG23522-01 / NIA NIH HHS MC_U106179471 / Medical Research Council RFP-NHLBI-WH-11-10 / WHI NIH HHS HHSN268200900009C / WHI NIH HHS N01-HC-65226 / NHLBI NIH HHS RG/07/008/23674 / British Heart Foundation Z01 AG000954 / Intramural NIH HHS MC_U123092721 / Medical Research Council N01HC-95168 / NHLBI NIH HHS G19/35 / Medical Research Council R01 LM010098 / NLM NIH HHS N01HC-95160 / NHLBI NIH HHS LM010098 / NLM NIH HHS MC_U123092720 / Medical Research Council G0600705 / Medical Research Council N01HC-95163 / NHLBI NIH HHS G8802774 / Medical Research Council RG/08/013/25942 / British Heart Foundation R01 NS042733 / NINDS NIH HHS N01HC95160 / NHLBI NIH HHS MC_UP_A100_1003 / Medical Research Council RG/04/003 / British Heart Foundation N01HC-95166 / NHLBI NIH HHS 081081/Z/06/Z / Wellcome Trust UL1 RR024156 / NCRR NIH HHS AG1764406S1 / NIA NIH HHS N01HC-95159 / NHLBI NIH HHS AG000954-06 / NIA NIH HHS R01 NS42733 / NINDS NIH HHS HHSN268200900009C / PHS HHS R37 AG013196 / NIA NIH HHS PG/09/022/26739 / British Heart Foundation
Language: English
Date published: 03/31/2012
Academic Unit: Epidemiology; Internal Medicine
Record Identifier: 9983995141202771

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