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

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, Kawah Li, Jutta Palmen, Philip Howard, Jackie A. Cooper, Fotios Drenos, John HardyMichael 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 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 Maitland-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 R Fowkes, Timothy M. Frayling, Jackie 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

Research output: Contribution to journalArticle

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
Externally publishedYes

Fingerprint

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)

Cite this

Swerdlow, D. I., Holmes, M. V., Kuchenbaecker, K. B., Engmann, J. E. L., Shah, T., Sofat, R., ... Casas, J. P. (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. / Swerdlow, Daniel I.; Holmes, Michael V.; Kuchenbaecker, Karoline B.; Engmann, Jorgen E L; Shah, Tina; Sofat, Reecha; Guo, Yiran; Chung, Christina; Peasey, Anne; Pfister, Roman; Mooijaart, Simon P.; Ireland, Helen A.; Leusink, Maarten; Langenberg, Claudia; Li, Kawah; 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; Houlston, Richard; 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; Hubacek, Jaroslav A.; Kubinova, Ruzena; Baceviciene, Migle; Tamosiunas, Abdonas; Pajak, Andrzej; Topor-Madry, Roman; Malyutina, Sofia; Baldassarre, Damiano; Sennblad, Bengt; Tremoli, Elena; De Faire, Ulf; Ferrucci, Luigi; Bandenelli, Stefania; Tanaka, Toshiko; Meschia, James F.; Singleton, Andrew; Navis, Gerjan; Leach, Irene Mateo; Bakker, Stephan J L; Gansevoort, Ron T.; Ford, Ian; Epstein, Stephen E.; Burnett, Mary Susan; Devaney, Joe M.; Jukema, J. Wouter; Westendorp, Rudi G J; De Borst, Gert Jan; Van Der Graaf, Yolanda; De Jong, Pim A.; Maitland-Van Der Zee, Anke Hilse; Klungel, Olaf H.; De Boer, Anthonius; Doevendans, Pieter A.; Stephens, Jeffrey W.; Eaton, Charles B.; Robinson, Jennifer G.; Manson, Joann E.; Fowkes, F. Gerry R; Frayling, Timothy M.; Price, Jackie; Whincup, Peter H.; Morris, Richard W.; Lawlor, Debbie A.; Smith, George Davey; Ben-Shlomo, Yoav; Redline, Susan; Lange, Leslie A.; Kumari, Meena; Wareham, Nick J.; Verschuren, W. M Monique; Benjamin, Emelia J.; Whittaker, John C.; 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.; Casas, Juan Pablo.

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

Research output: Contribution to journalArticle

Swerdlow, DI, Holmes, MV, Kuchenbaecker, KB, Engmann, JEL, Shah, T, Sofat, R, Guo, Y, Chung, C, Peasey, A, Pfister, R, Mooijaart, SP, Ireland, HA, Leusink, M, Langenberg, C, Li, K, Palmen, J, Howard, P, Cooper, JA, Drenos, F, Hardy, J, Nalls, MA, Li, YR, Lowe, G, Stewart, M, Bielinski, SJ, Peto, J, Timpson, NJ, Gallacher, J, Dunlop, M, Houlston, R, Tomlinson, I, Tzoulaki, I, Luan, JA, Boer, JMA, Forouhi, NG, Onland-Moret, NC, Van Der Schouw, YT, Schnabel, R, Hubacek, JA, Kubinova, R, Baceviciene, M, Tamosiunas, A, Pajak, A, Topor-Madry, R, Malyutina, S, Baldassarre, D, Sennblad, B, Tremoli, E, De Faire, U, Ferrucci, L, Bandenelli, S, Tanaka, T, Meschia, JF, Singleton, A, Navis, G, Leach, IM, Bakker, SJL, Gansevoort, RT, Ford, I, Epstein, SE, Burnett, MS, Devaney, JM, Jukema, JW, Westendorp, RGJ, De Borst, GJ, Van Der Graaf, Y, De Jong, PA, Maitland-Van Der Zee, AH, Klungel, OH, De Boer, A, Doevendans, PA, Stephens, JW, Eaton, CB, Robinson, JG, Manson, JE, Fowkes, FGR, Frayling, TM, Price, J, Whincup, PH, Morris, RW, Lawlor, DA, Smith, GD, Ben-Shlomo, Y, Redline, S, Lange, LA, Kumari, M, Wareham, NJ, Verschuren, WMM, Benjamin, EJ, Whittaker, JC, Hamsten, A, Dudbridge, F, Delaney, JAC, Wong, A, Kuh, D, Hardy, R, Castillo, BA, Connolly, JJ, Van Der Harst, P, Brunner, EJ, Marmot, MG, Wassel, CL, Humphries, SE, Talmud, PJ, Kivimaki, M, Asselbergs, FW, Voevoda, M, Bobak, M, Pikhart, H, Wilson, JG, Hakonarson, H, Reiner, AP, Keating, BJ, Sattar, N, Hingorani, AD & Casas, JP 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
Swerdlow DI, Holmes MV, Kuchenbaecker KB, Engmann JEL, Shah T, Sofat R et al. 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
Swerdlow, Daniel I. ; Holmes, Michael V. ; Kuchenbaecker, Karoline B. ; Engmann, Jorgen E L ; Shah, Tina ; Sofat, Reecha ; Guo, Yiran ; Chung, Christina ; Peasey, Anne ; Pfister, Roman ; Mooijaart, Simon P. ; Ireland, Helen A. ; Leusink, Maarten ; Langenberg, Claudia ; Li, Kawah ; 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 ; Houlston, Richard ; 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 ; Hubacek, Jaroslav A. ; Kubinova, Ruzena ; Baceviciene, Migle ; Tamosiunas, Abdonas ; Pajak, Andrzej ; Topor-Madry, Roman ; Malyutina, Sofia ; Baldassarre, Damiano ; Sennblad, Bengt ; Tremoli, Elena ; De Faire, Ulf ; Ferrucci, Luigi ; Bandenelli, Stefania ; Tanaka, Toshiko ; Meschia, James F. ; Singleton, Andrew ; Navis, Gerjan ; Leach, Irene Mateo ; Bakker, Stephan J L ; Gansevoort, Ron T. ; Ford, Ian ; Epstein, Stephen E. ; Burnett, Mary Susan ; Devaney, Joe M. ; Jukema, J. Wouter ; Westendorp, Rudi G J ; De Borst, Gert Jan ; Van Der Graaf, Yolanda ; De Jong, Pim A. ; Maitland-Van Der Zee, Anke Hilse ; Klungel, Olaf H. ; De Boer, Anthonius ; Doevendans, Pieter A. ; Stephens, Jeffrey W. ; Eaton, Charles B. ; Robinson, Jennifer G. ; Manson, Joann E. ; Fowkes, F. Gerry R ; Frayling, Timothy M. ; Price, Jackie ; Whincup, Peter H. ; Morris, Richard W. ; Lawlor, Debbie A. ; Smith, George Davey ; Ben-Shlomo, Yoav ; Redline, Susan ; Lange, Leslie A. ; Kumari, Meena ; Wareham, Nick J. ; Verschuren, W. M Monique ; Benjamin, Emelia J. ; Whittaker, John C. ; 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. ; Casas, Juan Pablo. / 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.
@article{12801eaa2233460c822f3fdf618ba52f,
title = "The interleukin-6 receptor as a target for prevention of coronary heart disease: A mendelian randomisation analysis",
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.",
author = "Swerdlow, {Daniel I.} and Holmes, {Michael V.} and Kuchenbaecker, {Karoline B.} and Engmann, {Jorgen E L} and Tina Shah and Reecha Sofat and Yiran Guo and Christina Chung and Anne Peasey and Roman Pfister and Mooijaart, {Simon P.} and Ireland, {Helen A.} and Maarten Leusink and Claudia Langenberg and Kawah Li and Jutta Palmen and Philip Howard and Cooper, {Jackie A.} and Fotios Drenos and John Hardy and Nalls, {Michael A.} and Li, {Yun Rose} and Gordon Lowe and Marlene Stewart and Bielinski, {Suzette J.} and Julian Peto and Timpson, {Nicholas J.} and John Gallacher and Malcolm Dunlop and Richard Houlston and Ian Tomlinson and Ioanna Tzoulaki and Jian'An Luan and Boer, {Jolanda M A} and Forouhi, {Nita G.} and Onland-Moret, {N. Charlotte} and {Van Der Schouw}, {Yvonne T.} and Renate Schnabel and Hubacek, {Jaroslav A.} and Ruzena Kubinova and Migle Baceviciene and Abdonas Tamosiunas and Andrzej Pajak and Roman Topor-Madry and Sofia Malyutina and Damiano Baldassarre and Bengt Sennblad and Elena Tremoli and {De Faire}, Ulf and Luigi Ferrucci and Stefania Bandenelli and Toshiko Tanaka and Meschia, {James F.} and Andrew Singleton and Gerjan Navis and Leach, {Irene Mateo} and Bakker, {Stephan J L} and Gansevoort, {Ron T.} and Ian Ford and Epstein, {Stephen E.} and Burnett, {Mary Susan} and Devaney, {Joe M.} and Jukema, {J. Wouter} and Westendorp, {Rudi G J} and {De Borst}, {Gert Jan} and {Van Der Graaf}, Yolanda and {De Jong}, {Pim A.} and {Maitland-Van Der Zee}, {Anke Hilse} and Klungel, {Olaf H.} and {De Boer}, Anthonius and Doevendans, {Pieter A.} and Stephens, {Jeffrey W.} and Eaton, {Charles B.} and Robinson, {Jennifer G.} and Manson, {Joann E.} and Fowkes, {F. Gerry R} and Frayling, {Timothy M.} and Jackie Price and Whincup, {Peter H.} and Morris, {Richard W.} and Lawlor, {Debbie A.} and Smith, {George Davey} and Yoav Ben-Shlomo and Susan Redline and Lange, {Leslie A.} and Meena Kumari and Wareham, {Nick J.} and Verschuren, {W. M Monique} and Benjamin, {Emelia J.} and Whittaker, {John C.} and Anders Hamsten and Frank Dudbridge and Delaney, {J. A Chris} and Andrew Wong and Diana Kuh and Rebecca Hardy and Castillo, {Berta Almoguera} and Connolly, {John J.} and {Van Der Harst}, Pim and Brunner, {Eric J.} and Marmot, {Michael G.} and Wassel, {Christina L.} and Humphries, {Steve E.} and Talmud, {Philippa J.} and Mika Kivimaki and Asselbergs, {Folkert W.} and Mikhail Voevoda and Martin Bobak and Hynek Pikhart and Wilson, {James G.} and Hakon Hakonarson and Reiner, {Alex P.} and Keating, {Brendan J.} and Naveed Sattar and Hingorani, {Aroon D.} and Casas, {Juan Pablo}",
year = "2012",
month = "3",
day = "1",
doi = "10.1016/S0140-6736(12)60110-X",
language = "English (US)",
volume = "379",
pages = "1214--1224",
journal = "The Lancet",
issn = "0140-6736",
publisher = "Elsevier Limited",
number = "9822",

}

TY - JOUR

T1 - The interleukin-6 receptor as a target for prevention of coronary heart disease

T2 - A mendelian randomisation analysis

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 - Ferrucci, Luigi

AU - Bandenelli, Stefania

AU - Tanaka, Toshiko

AU - Meschia, James F.

AU - Singleton, Andrew

AU - Navis, Gerjan

AU - Leach, Irene Mateo

AU - Bakker, Stephan J L

AU - Gansevoort, Ron T.

AU - Ford, Ian

AU - Epstein, Stephen E.

AU - Burnett, Mary Susan

AU - Devaney, Joe M.

AU - Jukema, J. Wouter

AU - Westendorp, Rudi G J

AU - De Borst, Gert Jan

AU - Van Der Graaf, Yolanda

AU - De Jong, Pim A.

AU - Maitland-Van Der Zee, Anke Hilse

AU - Klungel, Olaf H.

AU - De Boer, Anthonius

AU - Doevendans, Pieter A.

AU - Stephens, Jeffrey W.

AU - Eaton, Charles B.

AU - Robinson, Jennifer G.

AU - Manson, Joann E.

AU - Fowkes, F. Gerry R

AU - Frayling, Timothy M.

AU - Price, Jackie

AU - Whincup, Peter H.

AU - Morris, Richard W.

AU - Lawlor, Debbie A.

AU - Smith, George Davey

AU - Ben-Shlomo, Yoav

AU - Redline, Susan

AU - Lange, Leslie A.

AU - Kumari, Meena

AU - Wareham, Nick J.

AU - Verschuren, W. M Monique

AU - Benjamin, Emelia J.

AU - Whittaker, John C.

AU - Hamsten, Anders

AU - Dudbridge, Frank

AU - Delaney, J. A Chris

AU - Wong, Andrew

AU - Kuh, Diana

AU - Hardy, Rebecca

AU - Castillo, Berta Almoguera

AU - Connolly, John J.

AU - Van Der Harst, Pim

AU - Brunner, Eric J.

AU - Marmot, Michael G.

AU - Wassel, Christina L.

AU - Humphries, Steve E.

AU - Talmud, Philippa J.

AU - Kivimaki, Mika

AU - Asselbergs, Folkert W.

AU - Voevoda, Mikhail

AU - Bobak, Martin

AU - Pikhart, Hynek

AU - Wilson, James G.

AU - Hakonarson, Hakon

AU - Reiner, Alex P.

AU - Keating, Brendan J.

AU - Sattar, Naveed

AU - Hingorani, Aroon D.

AU - Casas, Juan Pablo

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.

UR - http://www.scopus.com/inward/record.url?scp=84859215358&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84859215358&partnerID=8YFLogxK

U2 - 10.1016/S0140-6736(12)60110-X

DO - 10.1016/S0140-6736(12)60110-X

M3 - Article

C2 - 22421340

AN - SCOPUS:84859215358

VL - 379

SP - 1214

EP - 1224

JO - The Lancet

JF - The Lancet

SN - 0140-6736

IS - 9822

ER -