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

Summary 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 infla... Full description

Journal Title: The Lancet (British edition) 2012, Vol.379 (9822), p.1214-1224
Main Author: Holmes, Michael V
Other Authors: Kuchenbaecker, Karoline B , Shah, Tina , Guo, Yiran , Chung, Christina , Peasey, Anne , Pfister, Roman , Mooijaart, Simon P , Ireland, Helen A , Leusink, Maarten , Langenberg, Claudia , Li, Ka Wah , Palmen, Jutta , Howard, Philip , Cooper, Jackie A , Drenos, Fotios , Hardy, John , Nalls, Michael A , Li, Yun Rose , Lowe, Gordon , Stewart, Marlene , Bielinski, Suzette J , Peto, Julian , Timpson, Nicholas J , Gallacher, John , Dunlop, Malcolm , Tomlinson, Ian , Tzoulaki, Ioanna , Luan, Jian'an , Boer, Jolanda M A , Forouhi, Nita G , Onland-Moret, N Charlotte , van der Schouw, Yvonne T , Schnabel, Renate B , Hubacek, Jaroslav A , Kubinova, Ruzena , Pajak, Andrzej , Malyutina, Sofia , Baldassarre, Damiano , Sennblad, Bengt , Tremoli, Elena , Ferrucci, Luigi , Bandenelli, Stefania , Meschia, James F , Singleton, Andrew , Navis, Gerjan , Mateo Leach, Irene , Bakker, Stephan J L , Gansevoort, Ron T , Burnett, Mary Susan , Devaney, Joe M , Jukema, J Wouter , Westendorp, Rudi G J , Jan de Borst, Gert , van der Graaf, Yolanda , de Jong, Pim A , Mailand-van der Zee, Anke-Hilse , Klungel, Olaf H , de Boer, Anthonius , Doevendans, Pieter A , Stephens, Jeffrey W , Eaton, Charles B , Robinson, Jennifer G , Fowkes, F Gerry , Frayling, Timonthy M , Whincup, Peter H , Morris, Richard W , Lawlor, Debbie A , Smith, George Davey , Ben-Shlomo, Yoav , Redline, Susan , Kumari, Meena , Wareham, Nick J , Verschuren, W M Monique , Benjamin, Emelia J , Hamsten, Anders , Dudbridge, Frank , Delaney, J A Chris , Wong, Andrew , Kuh, Diana , Hardy, Rebecca , Castillo, Berta Almoguera , Connolly, John J , van der Harst, Pim , Brunner, Eric J , Marmot, Michael G , Wassel, Christina L , Humphries, Steve E , Talmud, Philippa J , Kivimaki, Mika , Asselbergs, Folkert W , Voevoda, Mikhail , Bobak, Martin , Pikhart, Hynek , Wilson, James G , Hakonarson, Hakon , Reiner, Alex P , Keating, Brendan J , Sattar, Naveed , Hingorani, Aroon D
Format: Electronic Article Electronic Article
Language: English
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Quelle: Alma/SFX Local Collection
Publisher: Kidlington: Elsevier Ltd
ID: ISSN: 0140-6736
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title: The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis
format: Article
creator:
  • Holmes, Michael V
  • Kuchenbaecker, Karoline B
  • Shah, Tina
  • Guo, Yiran
  • Chung, Christina
  • Peasey, Anne
  • Pfister, Roman
  • Mooijaart, Simon P
  • Ireland, Helen A
  • Leusink, Maarten
  • Langenberg, Claudia
  • Li, Ka Wah
  • Palmen, Jutta
  • Howard, Philip
  • Cooper, Jackie A
  • Drenos, Fotios
  • Hardy, John
  • Nalls, Michael A
  • Li, Yun Rose
  • Lowe, Gordon
  • Stewart, Marlene
  • Bielinski, Suzette J
  • Peto, Julian
  • Timpson, Nicholas J
  • Gallacher, John
  • Dunlop, Malcolm
  • Tomlinson, Ian
  • Tzoulaki, Ioanna
  • Luan, Jian'an
  • Boer, Jolanda M A
  • Forouhi, Nita G
  • Onland-Moret, N Charlotte
  • van der Schouw, Yvonne T
  • Schnabel, Renate B
  • Hubacek, Jaroslav A
  • Kubinova, Ruzena
  • Pajak, Andrzej
  • Malyutina, Sofia
  • Baldassarre, Damiano
  • Sennblad, Bengt
  • Tremoli, Elena
  • Ferrucci, Luigi
  • Bandenelli, Stefania
  • Meschia, James F
  • Singleton, Andrew
  • Navis, Gerjan
  • Mateo Leach, Irene
  • Bakker, Stephan J L
  • Gansevoort, Ron T
  • Burnett, Mary Susan
  • Devaney, Joe M
  • Jukema, J Wouter
  • Westendorp, Rudi G J
  • Jan de Borst, Gert
  • van der Graaf, Yolanda
  • de Jong, Pim A
  • Mailand-van der Zee, Anke-Hilse
  • Klungel, Olaf H
  • de Boer, Anthonius
  • Doevendans, Pieter A
  • Stephens, Jeffrey W
  • Eaton, Charles B
  • Robinson, Jennifer G
  • Fowkes, F Gerry
  • Frayling, Timonthy M
  • Whincup, Peter H
  • Morris, Richard W
  • Lawlor, Debbie A
  • Smith, George Davey
  • Ben-Shlomo, Yoav
  • Redline, Susan
  • Kumari, Meena
  • Wareham, Nick J
  • Verschuren, W M Monique
  • Benjamin, Emelia J
  • Hamsten, Anders
  • Dudbridge, Frank
  • Delaney, J A Chris
  • Wong, Andrew
  • Kuh, Diana
  • Hardy, Rebecca
  • Castillo, Berta Almoguera
  • Connolly, John J
  • van der Harst, Pim
  • Brunner, Eric J
  • Marmot, Michael G
  • Wassel, Christina L
  • Humphries, Steve E
  • Talmud, Philippa J
  • Kivimaki, Mika
  • Asselbergs, Folkert W
  • Voevoda, Mikhail
  • Bobak, Martin
  • Pikhart, Hynek
  • Wilson, James G
  • Hakonarson, Hakon
  • Reiner, Alex P
  • Keating, Brendan J
  • Sattar, Naveed
  • Hingorani, Aroon D
subjects:
  • Analysis
  • Antibodies, Monoclonal, Humanized - adverse effects
  • Antibodies, Monoclonal, Humanized - therapeutic use
  • Articles
  • atira
  • Biological and medical sciences
  • Cancer
  • Cardiology. Vascular system
  • Cardiovascular disease
  • Cholesterol
  • Coronary Disease - genetics
  • Coronary Disease - prevention & control
  • Coronary heart disease
  • Cytokine receptors
  • Drug therapy
  • Extramural
  • Gene Frequency - genetics
  • General aspects
  • Genetic aspects
  • Genetic Association Studies
  • Genetic Variation - genetics
  • Genotype
  • Gov't
  • Health aspects
  • Heart
  • Humans
  • Inflammation Mediators - blood
  • Interleukin-6
  • Internal Medicine
  • Intramural
  • Journal Article
  • Medical research
  • Medical sciences
  • Medicin och hälsovetenskap
  • Mendelian Randomization Analysis
  • Meta
  • Non
  • Phenotype
  • Physiological aspects
  • Polymorphism, Single Nucleotide - genetics
  • Prevention
  • pubmedpublicationtype
  • pure
  • Randomized Controlled Trials as Topic
  • Receptors, Interleukin-6 - antagonists & inhibitors
  • Receptors, Interleukin-6 - genetics
  • Research
  • Research Support
  • researchoutput
  • Risk factors
  • Signal Transduction - drug effects
  • Signal Transduction - genetics
  • Studies
  • Treatment Outcome
ispartof: The Lancet (British edition), 2012, Vol.379 (9822), p.1214-1224
description: Summary 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 Developmen
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0140-6736
fulltext: fulltext
issn:
  • 0140-6736
  • 1474-547X
  • 1474-547X
url: Link


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titleThe interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis
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creatorHolmes, Michael V ; Kuchenbaecker, Karoline B ; Shah, Tina ; Guo, Yiran ; Chung, Christina ; Peasey, Anne ; Pfister, Roman ; Mooijaart, Simon P ; Ireland, Helen A ; Leusink, Maarten ; Langenberg, Claudia ; Li, Ka Wah ; Palmen, Jutta ; Howard, Philip ; Cooper, Jackie A ; Drenos, Fotios ; Hardy, John ; Nalls, Michael A ; Li, Yun Rose ; Lowe, Gordon ; Stewart, Marlene ; Bielinski, Suzette J ; Peto, Julian ; Timpson, Nicholas J ; Gallacher, John ; Dunlop, Malcolm ; Tomlinson, Ian ; Tzoulaki, Ioanna ; Luan, Jian'an ; Boer, Jolanda M A ; Forouhi, Nita G ; Onland-Moret, N Charlotte ; van der Schouw, Yvonne T ; Schnabel, Renate B ; Hubacek, Jaroslav A ; Kubinova, Ruzena ; Pajak, Andrzej ; Malyutina, Sofia ; Baldassarre, Damiano ; Sennblad, Bengt ; Tremoli, Elena ; Ferrucci, Luigi ; Bandenelli, Stefania ; Meschia, James F ; Singleton, Andrew ; Navis, Gerjan ; Mateo Leach, Irene ; Bakker, Stephan J L ; Gansevoort, Ron T ; Burnett, Mary Susan ; Devaney, Joe M ; Jukema, J Wouter ; Westendorp, Rudi G J ; Jan de Borst, Gert ; van der Graaf, Yolanda ; de Jong, Pim A ; Mailand-van der Zee, Anke-Hilse ; Klungel, Olaf H ; de Boer, Anthonius ; Doevendans, Pieter A ; Stephens, Jeffrey W ; Eaton, Charles B ; Robinson, Jennifer G ; Fowkes, F Gerry ; Frayling, Timonthy M ; Whincup, Peter H ; Morris, Richard W ; Lawlor, Debbie A ; Smith, George Davey ; Ben-Shlomo, Yoav ; Redline, Susan ; Kumari, Meena ; Wareham, Nick J ; Verschuren, W M Monique ; Benjamin, Emelia J ; Hamsten, Anders ; Dudbridge, Frank ; Delaney, J A Chris ; Wong, Andrew ; Kuh, Diana ; Hardy, Rebecca ; Castillo, Berta Almoguera ; Connolly, John J ; van der Harst, Pim ; Brunner, Eric J ; Marmot, Michael G ; Wassel, Christina L ; Humphries, Steve E ; Talmud, Philippa J ; Kivimaki, Mika ; Asselbergs, Folkert W ; Voevoda, Mikhail ; Bobak, Martin ; Pikhart, Hynek ; Wilson, James G ; Hakonarson, Hakon ; Reiner, Alex P ; Keating, Brendan J ; Sattar, Naveed ; Hingorani, Aroon D
creatorcontribHolmes, Michael V ; Kuchenbaecker, Karoline B ; Shah, Tina ; Guo, Yiran ; Chung, Christina ; Peasey, Anne ; Pfister, Roman ; Mooijaart, Simon P ; Ireland, Helen A ; Leusink, Maarten ; Langenberg, Claudia ; Li, Ka Wah ; Palmen, Jutta ; Howard, Philip ; Cooper, Jackie A ; Drenos, Fotios ; Hardy, John ; Nalls, Michael A ; Li, Yun Rose ; Lowe, Gordon ; Stewart, Marlene ; Bielinski, Suzette J ; Peto, Julian ; Timpson, Nicholas J ; Gallacher, John ; Dunlop, Malcolm ; Tomlinson, Ian ; Tzoulaki, Ioanna ; Luan, Jian'an ; Boer, Jolanda M A ; Forouhi, Nita G ; Onland-Moret, N Charlotte ; van der Schouw, Yvonne T ; Schnabel, Renate B ; Hubacek, Jaroslav A ; Kubinova, Ruzena ; Pajak, Andrzej ; Malyutina, Sofia ; Baldassarre, Damiano ; Sennblad, Bengt ; Tremoli, Elena ; Ferrucci, Luigi ; Bandenelli, Stefania ; Meschia, James F ; Singleton, Andrew ; Navis, Gerjan ; Mateo Leach, Irene ; Bakker, Stephan J L ; Gansevoort, Ron T ; Burnett, Mary Susan ; Devaney, Joe M ; Jukema, J Wouter ; Westendorp, Rudi G J ; Jan de Borst, Gert ; van der Graaf, Yolanda ; de Jong, Pim A ; Mailand-van der Zee, Anke-Hilse ; Klungel, Olaf H ; de Boer, Anthonius ; Doevendans, Pieter A ; Stephens, Jeffrey W ; Eaton, Charles B ; Robinson, Jennifer G ; Fowkes, F Gerry ; Frayling, Timonthy M ; Whincup, Peter H ; Morris, Richard W ; Lawlor, Debbie A ; Smith, George Davey ; Ben-Shlomo, Yoav ; Redline, Susan ; Kumari, Meena ; Wareham, Nick J ; Verschuren, W M Monique ; Benjamin, Emelia J ; Hamsten, Anders ; Dudbridge, Frank ; Delaney, J A Chris ; Wong, Andrew ; Kuh, Diana ; Hardy, Rebecca ; Castillo, Berta Almoguera ; Connolly, John J ; van der Harst, Pim ; Brunner, Eric J ; Marmot, Michael G ; Wassel, Christina L ; Humphries, Steve E ; Talmud, Philippa J ; Kivimaki, Mika ; Asselbergs, Folkert W ; Voevoda, Mikhail ; Bobak, Martin ; Pikhart, Hynek ; Wilson, James G ; Hakonarson, Hakon ; Reiner, Alex P ; Keating, Brendan J ; Sattar, Naveed ; Hingorani, Aroon D ; The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium ; Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium
descriptionSummary 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.
identifier
0ISSN: 0140-6736
1ISSN: 1474-547X
2EISSN: 1474-547X
3DOI: 10.1016/S0140-6736(12)60110-X
4PMID: 22421340
5CODEN: LANCAO
languageeng
publisherKidlington: Elsevier Ltd
subjectAnalysis ; Antibodies, Monoclonal, Humanized - adverse effects ; Antibodies, Monoclonal, Humanized - therapeutic use ; Articles ; atira ; Biological and medical sciences ; Cancer ; Cardiology. Vascular system ; Cardiovascular disease ; Cholesterol ; Coronary Disease - genetics ; Coronary Disease - prevention & control ; Coronary heart disease ; Cytokine receptors ; Drug therapy ; Extramural ; Gene Frequency - genetics ; General aspects ; Genetic aspects ; Genetic Association Studies ; Genetic Variation - genetics ; Genotype ; Gov't ; Health aspects ; Heart ; Humans ; Inflammation Mediators - blood ; Interleukin-6 ; Internal Medicine ; Intramural ; Journal Article ; Medical research ; Medical sciences ; Medicin och hälsovetenskap ; Mendelian Randomization Analysis ; Meta ; Non ; Phenotype ; Physiological aspects ; Polymorphism, Single Nucleotide - genetics ; Prevention ; pubmedpublicationtype ; pure ; Randomized Controlled Trials as Topic ; Receptors, Interleukin-6 - antagonists & inhibitors ; Receptors, Interleukin-6 - genetics ; Research ; Research Support ; researchoutput ; Risk factors ; Signal Transduction - drug effects ; Signal Transduction - genetics ; Studies ; Treatment Outcome
ispartofThe Lancet (British edition), 2012, Vol.379 (9822), p.1214-1224
rights
0Elsevier Ltd
12012 Elsevier Ltd
2info:eu-repo/semantics/openAccess
32015 INIST-CNRS
4Copyright © 2012 Elsevier Ltd. All rights reserved.
5COPYRIGHT 2012 Elsevier B.V.
6Copyright Elsevier Limited Mar 31-Apr 6, 2012
72012 Elsevier Ltd. All rights reserved. 2012 Elsevier Ltd
lds50peer_reviewed
oafree_for_read
citedbyFETCH-LOGICAL-1938t-87b85dde6154127a12df8fa4ee9443e4bb1b01fb4eafa49c273fcf8c655df0183
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creatorcontrib
0Holmes, Michael V
1Kuchenbaecker, Karoline B
2Shah, Tina
3Guo, Yiran
4Chung, Christina
5Peasey, Anne
6Pfister, Roman
7Mooijaart, Simon P
8Ireland, Helen A
9Leusink, Maarten
10Langenberg, Claudia
11Li, Ka Wah
12Palmen, Jutta
13Howard, Philip
14Cooper, Jackie A
15Drenos, Fotios
16Hardy, John
17Nalls, Michael A
18Li, Yun Rose
19Lowe, Gordon
20Stewart, Marlene
21Bielinski, Suzette J
22Peto, Julian
23Timpson, Nicholas J
24Gallacher, John
25Dunlop, Malcolm
26Tomlinson, Ian
27Tzoulaki, Ioanna
28Luan, Jian'an
29Boer, Jolanda M A
30Forouhi, Nita G
31Onland-Moret, N Charlotte
32van der Schouw, Yvonne T
33Schnabel, Renate B
34Hubacek, Jaroslav A
35Kubinova, Ruzena
36Pajak, Andrzej
37Malyutina, Sofia
38Baldassarre, Damiano
39Sennblad, Bengt
40Tremoli, Elena
41Ferrucci, Luigi
42Bandenelli, Stefania
43Meschia, James F
44Singleton, Andrew
45Navis, Gerjan
46Mateo Leach, Irene
47Bakker, Stephan J L
48Gansevoort, Ron T
49Burnett, Mary Susan
50Devaney, Joe M
51Jukema, J Wouter
52Westendorp, Rudi G J
53Jan de Borst, Gert
54van der Graaf, Yolanda
55de Jong, Pim A
56Mailand-van der Zee, Anke-Hilse
57Klungel, Olaf H
58de Boer, Anthonius
59Doevendans, Pieter A
60Stephens, Jeffrey W
61Eaton, Charles B
62Robinson, Jennifer G
63Fowkes, F Gerry
64Frayling, Timonthy M
65Whincup, Peter H
66Morris, Richard W
67Lawlor, Debbie A
68Smith, George Davey
69Ben-Shlomo, Yoav
70Redline, Susan
71Kumari, Meena
72Wareham, Nick J
73Verschuren, W M Monique
74Benjamin, Emelia J
75Hamsten, Anders
76Dudbridge, Frank
77Delaney, J A Chris
78Wong, Andrew
79Kuh, Diana
80Hardy, Rebecca
81Castillo, Berta Almoguera
82Connolly, John J
83van der Harst, Pim
84Brunner, Eric J
85Marmot, Michael G
86Wassel, Christina L
87Humphries, Steve E
88Talmud, Philippa J
89Kivimaki, Mika
90Asselbergs, Folkert W
91Voevoda, Mikhail
92Bobak, Martin
93Pikhart, Hynek
94Wilson, James G
95Hakonarson, Hakon
96Reiner, Alex P
97Keating, Brendan J
98Sattar, Naveed
99Hingorani, Aroon D
100The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium
101Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium
title
0The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis
1The Lancet (British edition)
addtitleLancet
descriptionSummary 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.
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6Cancer
7Cardiology. Vascular system
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9Cholesterol
10Coronary Disease - genetics
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13Cytokine receptors
14Drug therapy
15Extramural
16Gene Frequency - genetics
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19Genetic Association Studies
20Genetic Variation - genetics
21Genotype
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1Kuchenbaecker, Karoline B
2Shah, Tina
3Guo, Yiran
4Chung, Christina
5Peasey, Anne
6Pfister, Roman
7Mooijaart, Simon P
8Ireland, Helen A
9Leusink, Maarten
10Langenberg, Claudia
11Li, Ka Wah
12Palmen, Jutta
13Howard, Philip
14Cooper, Jackie A
15Drenos, Fotios
16Hardy, John
17Nalls, Michael A
18Li, Yun Rose
19Lowe, Gordon
20Stewart, Marlene
21Bielinski, Suzette J
22Peto, Julian
23Timpson, Nicholas J
24Gallacher, John
25Dunlop, Malcolm
26Tomlinson, Ian
27Tzoulaki, Ioanna
28Luan, Jian'an
29Boer, Jolanda M A
30Forouhi, Nita G
31Onland-Moret, N Charlotte
32van der Schouw, Yvonne T
33Schnabel, Renate B
34Hubacek, Jaroslav A
35Kubinova, Ruzena
36Pajak, Andrzej
37Malyutina, Sofia
38Baldassarre, Damiano
39Sennblad, Bengt
40Tremoli, Elena
41Ferrucci, Luigi
42Bandenelli, Stefania
43Meschia, James F
44Singleton, Andrew
45Navis, Gerjan
46Mateo Leach, Irene
47Bakker, Stephan J L
48Gansevoort, Ron T
49Burnett, Mary Susan
50Devaney, Joe M
51Jukema, J Wouter
52Westendorp, Rudi G J
53Jan de Borst, Gert
54van der Graaf, Yolanda
55de Jong, Pim A
56Mailand-van der Zee, Anke-Hilse
57Klungel, Olaf H
58de Boer, Anthonius
59Doevendans, Pieter A
60Stephens, Jeffrey W
61Eaton, Charles B
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63Fowkes, F Gerry
64Frayling, Timonthy M
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69Ben-Shlomo, Yoav
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83van der Harst, Pim
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86Wassel, Christina L
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91Voevoda, Mikhail
92Bobak, Martin
93Pikhart, Hynek
94Wilson, James G
95Hakonarson, Hakon
96Reiner, Alex P
97Keating, Brendan J
98Sattar, Naveed
99Hingorani, Aroon D
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titleThe interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis
authorHolmes, Michael V ; Kuchenbaecker, Karoline B ; Shah, Tina ; Guo, Yiran ; Chung, Christina ; Peasey, Anne ; Pfister, Roman ; Mooijaart, Simon P ; Ireland, Helen A ; Leusink, Maarten ; Langenberg, Claudia ; Li, Ka Wah ; Palmen, Jutta ; Howard, Philip ; Cooper, Jackie A ; Drenos, Fotios ; Hardy, John ; Nalls, Michael A ; Li, Yun Rose ; Lowe, Gordon ; Stewart, Marlene ; Bielinski, Suzette J ; Peto, Julian ; Timpson, Nicholas J ; Gallacher, John ; Dunlop, Malcolm ; Tomlinson, Ian ; Tzoulaki, Ioanna ; Luan, Jian'an ; Boer, Jolanda M A ; Forouhi, Nita G ; Onland-Moret, N Charlotte ; van der Schouw, Yvonne T ; Schnabel, Renate B ; Hubacek, Jaroslav A ; Kubinova, Ruzena ; Pajak, Andrzej ; Malyutina, Sofia ; Baldassarre, Damiano ; Sennblad, Bengt ; Tremoli, Elena ; Ferrucci, Luigi ; Bandenelli, Stefania ; Meschia, James F ; Singleton, Andrew ; Navis, Gerjan ; Mateo Leach, Irene ; Bakker, Stephan J L ; Gansevoort, Ron T ; Burnett, Mary Susan ; Devaney, Joe M ; Jukema, J Wouter ; Westendorp, Rudi G J ; Jan de Borst, Gert ; van der Graaf, Yolanda ; de Jong, Pim A ; Mailand-van der Zee, Anke-Hilse ; Klungel, Olaf H ; de Boer, Anthonius ; Doevendans, Pieter A ; Stephens, Jeffrey W ; Eaton, Charles B ; Robinson, Jennifer G ; Fowkes, F Gerry ; Frayling, Timonthy M ; Whincup, Peter H ; Morris, Richard W ; Lawlor, Debbie A ; Smith, George Davey ; Ben-Shlomo, Yoav ; Redline, Susan ; Kumari, Meena ; Wareham, Nick J ; Verschuren, W M Monique ; Benjamin, Emelia J ; Hamsten, Anders ; Dudbridge, Frank ; Delaney, J A Chris ; Wong, Andrew ; Kuh, Diana ; Hardy, Rebecca ; Castillo, Berta Almoguera ; Connolly, John J ; van der Harst, Pim ; Brunner, Eric J ; Marmot, Michael G ; Wassel, Christina L ; Humphries, Steve E ; Talmud, Philippa J ; Kivimaki, Mika ; Asselbergs, Folkert W ; Voevoda, Mikhail ; Bobak, Martin ; Pikhart, Hynek ; Wilson, James G ; Hakonarson, Hakon ; Reiner, Alex P ; Keating, Brendan J ; Sattar, Naveed ; Hingorani, Aroon D
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1Antibodies, Monoclonal, Humanized - adverse effects
2Antibodies, Monoclonal, Humanized - therapeutic use
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5Biological and medical sciences
6Cancer
7Cardiology. Vascular system
8Cardiovascular disease
9Cholesterol
10Coronary Disease - genetics
11Coronary Disease - prevention & control
12Coronary heart disease
13Cytokine receptors
14Drug therapy
15Extramural
16Gene Frequency - genetics
17General aspects
18Genetic aspects
19Genetic Association Studies
20Genetic Variation - genetics
21Genotype
22Gov't
23Health aspects
24Heart
25Humans
26Inflammation Mediators - blood
27Interleukin-6
28Internal Medicine
29Intramural
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31Medical research
32Medical sciences
33Medicin och hälsovetenskap
34Mendelian Randomization Analysis
35Meta
36Non
37Phenotype
38Physiological aspects
39Polymorphism, Single Nucleotide - genetics
40Prevention
41pubmedpublicationtype
42pure
43Randomized Controlled Trials as Topic
44Receptors, Interleukin-6 - antagonists & inhibitors
45Receptors, Interleukin-6 - genetics
46Research
47Research Support
48researchoutput
49Risk factors
50Signal Transduction - drug effects
51Signal Transduction - genetics
52Studies
53Treatment Outcome
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0Holmes, Michael V
1Kuchenbaecker, Karoline B
2Shah, Tina
3Guo, Yiran
4Chung, Christina
5Peasey, Anne
6Pfister, Roman
7Mooijaart, Simon P
8Ireland, Helen A
9Leusink, Maarten
10Langenberg, Claudia
11Li, Ka Wah
12Palmen, Jutta
13Howard, Philip
14Cooper, Jackie A
15Drenos, Fotios
16Hardy, John
17Nalls, Michael A
18Li, Yun Rose
19Lowe, Gordon
20Stewart, Marlene
21Bielinski, Suzette J
22Peto, Julian
23Timpson, Nicholas J
24Gallacher, John
25Dunlop, Malcolm
26Tomlinson, Ian
27Tzoulaki, Ioanna
28Luan, Jian'an
29Boer, Jolanda M A
30Forouhi, Nita G
31Onland-Moret, N Charlotte
32van der Schouw, Yvonne T
33Schnabel, Renate B
34Hubacek, Jaroslav A
35Kubinova, Ruzena
36Pajak, Andrzej
37Malyutina, Sofia
38Baldassarre, Damiano
39Sennblad, Bengt
40Tremoli, Elena
41Ferrucci, Luigi
42Bandenelli, Stefania
43Meschia, James F
44Singleton, Andrew
45Navis, Gerjan
46Mateo Leach, Irene
47Bakker, Stephan J L
48Gansevoort, Ron T
49Burnett, Mary Susan
50Devaney, Joe M
51Jukema, J Wouter
52Westendorp, Rudi G J
53Jan de Borst, Gert
54van der Graaf, Yolanda
55de Jong, Pim A
56Mailand-van der Zee, Anke-Hilse
57Klungel, Olaf H
58de Boer, Anthonius
59Doevendans, Pieter A
60Stephens, Jeffrey W
61Eaton, Charles B
62Robinson, Jennifer G
63Fowkes, F Gerry
64Frayling, Timonthy M
65Whincup, Peter H
66Morris, Richard W
67Lawlor, Debbie A
68Smith, George Davey
69Ben-Shlomo, Yoav
70Redline, Susan
71Kumari, Meena
72Wareham, Nick J
73Verschuren, W M Monique
74Benjamin, Emelia J
75Hamsten, Anders
76Dudbridge, Frank
77Delaney, J A Chris
78Wong, Andrew
79Kuh, Diana
80Hardy, Rebecca
81Castillo, Berta Almoguera
82Connolly, John J
83van der Harst, Pim
84Brunner, Eric J
85Marmot, Michael G
86Wassel, Christina L
87Humphries, Steve E
88Talmud, Philippa J
89Kivimaki, Mika
90Asselbergs, Folkert W
91Voevoda, Mikhail
92Bobak, Martin
93Pikhart, Hynek
94Wilson, James G
95Hakonarson, Hakon
96Reiner, Alex P
97Keating, Brendan J
98Sattar, Naveed
99Hingorani, Aroon D
100The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium
101Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium
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jtitleThe Lancet (British edition)
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fulltextfulltext
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au
0Holmes, Michael V
1Kuchenbaecker, Karoline B
2Shah, Tina
3Guo, Yiran
4Chung, Christina
5Peasey, Anne
6Pfister, Roman
7Mooijaart, Simon P
8Ireland, Helen A
9Leusink, Maarten
10Langenberg, Claudia
11Li, Ka Wah
12Palmen, Jutta
13Howard, Philip
14Cooper, Jackie A
15Drenos, Fotios
16Hardy, John
17Nalls, Michael A
18Li, Yun Rose
19Lowe, Gordon
20Stewart, Marlene
21Bielinski, Suzette J
22Peto, Julian
23Timpson, Nicholas J
24Gallacher, John
25Dunlop, Malcolm
26Tomlinson, Ian
27Tzoulaki, Ioanna
28Luan, Jian'an
29Boer, Jolanda M A
30Forouhi, Nita G
31Onland-Moret, N Charlotte
32van der Schouw, Yvonne T
33Schnabel, Renate B
34Hubacek, Jaroslav A
35Kubinova, Ruzena
36Pajak, Andrzej
37Malyutina, Sofia
38Baldassarre, Damiano
39Sennblad, Bengt
40Tremoli, Elena
41Ferrucci, Luigi
42Bandenelli, Stefania
43Meschia, James F
44Singleton, Andrew
45Navis, Gerjan
46Mateo Leach, Irene
47Bakker, Stephan J L
48Gansevoort, Ron T
49Burnett, Mary Susan
50Devaney, Joe M
51Jukema, J Wouter
52Westendorp, Rudi G J
53Jan de Borst, Gert
54van der Graaf, Yolanda
55de Jong, Pim A
56Mailand-van der Zee, Anke-Hilse
57Klungel, Olaf H
58de Boer, Anthonius
59Doevendans, Pieter A
60Stephens, Jeffrey W
61Eaton, Charles B
62Robinson, Jennifer G
63Fowkes, F Gerry
64Frayling, Timonthy M
65Whincup, Peter H
66Morris, Richard W
67Lawlor, Debbie A
68Smith, George Davey
69Ben-Shlomo, Yoav
70Redline, Susan
71Kumari, Meena
72Wareham, Nick J
73Verschuren, W M Monique
74Benjamin, Emelia J
75Hamsten, Anders
76Dudbridge, Frank
77Delaney, J A Chris
78Wong, Andrew
79Kuh, Diana
80Hardy, Rebecca
81Castillo, Berta Almoguera
82Connolly, John J
83van der Harst, Pim
84Brunner, Eric J
85Marmot, Michael G
86Wassel, Christina L
87Humphries, Steve E
88Talmud, Philippa J
89Kivimaki, Mika
90Asselbergs, Folkert W
91Voevoda, Mikhail
92Bobak, Martin
93Pikhart, Hynek
94Wilson, James G
95Hakonarson, Hakon
96Reiner, Alex P
97Keating, Brendan J
98Sattar, Naveed
99Hingorani, Aroon D
aucorp
0The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium
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atitleThe interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis
jtitleThe Lancet (British edition)
addtitleLancet
date2012
risdate2012
volume379
issue9822
spage1214
epage1224
pages1214-1224
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00140-6736
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abstractSummary 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.
copKidlington
pubElsevier Ltd
pmid22421340
doi10.1016/S0140-6736(12)60110-X
oafree_for_read