Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies

Nadeem Sarwar; Adam S Butterworth; Daniel F Freitag; John Gregson; Peter Willeit; Donal N Gorman; Pei Gao; Danish Saleheen; Augusto Rendon; Christopher P Nelson; Peter S Braund; Alistair S Hall; Daniel I Chasman; Anne Tybjærg-Hansen; John C Chambers; Emelia J Benjamin; Paul W Franks; Robert Clarke; Arthur A M Wilde; Mieke D Trip; Maristella Steri; Jacqueline C M Witteman; Lu Qi; C Ellen van der Schoot; Ulf de Faire; Jeanette Erdmann; Heather M Stringham; Wolfgang Koenig; Daniel J Rader; David Melzer; David Reich; Bruce M Psaty; Marcus E Kleber; Demosthenes B Panagiotakos; Johann Willeit; Patrik Wennberg; Mark Woodward; Svetlana Adamovic; Eric B Rimm; Tom W Meade; Richard F Gillum; Jonathan A Shaffer; Albert Hofman; Altan Onat; Johan Sundström; Sylvia Wassertheil-Smoller; Dan Mellström; John Gallacher; Kristine Højgaard Allin; Børge G Nordestgaard; IL6R Genetics Consortium Emerging Risk Factors Collaboration

doi:10.1016/S0140-6736(11)61931-4

Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies

Nadeem Sarwar, Adam S Butterworth, Daniel F Freitag, John Gregson, Peter Willeit, Donal N Gorman, Pei Gao, Danish Saleheen, Augusto Rendon, Christopher P Nelson, Peter S Braund, Alistair S Hall, Daniel I Chasman, Anne Tybjærg-Hansen, John C Chambers, Emelia J Benjamin, Paul W Franks, Robert Clarke, Arthur A M Wilde, Mieke D TripMaristella Steri, Jacqueline C M Witteman, Lu Qi, C Ellen van der Schoot, Ulf de Faire, Jeanette Erdmann, Heather M Stringham, Wolfgang Koenig, Daniel J Rader, David Melzer, David Reich, Bruce M Psaty, Marcus E Kleber, Demosthenes B Panagiotakos, Johann Willeit, Patrik Wennberg, Mark Woodward, Svetlana Adamovic, Eric B Rimm, Tom W Meade, Richard F Gillum, Jonathan A Shaffer, Albert Hofman, Altan Onat, Johan Sundström, Sylvia Wassertheil-Smoller, Dan Mellström, John Gallacher, Kristine Højgaard Allin, Børge G Nordestgaard, IL6R Genetics Consortium Emerging Risk Factors Collaboration

479 Citations (Scopus)

Abstract

Background: Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. Methods: In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. Findings: The minor allele frequency of Asp358Ala was 39. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3 (95 CI 30·4-38·2) and of interleukin 6 by 14·6 (10·7-18·4), and mean concentration of C-reactive protein was reduced by 7·5 (5·9-9·1) and of fibrinogen by 1·0 (0·7-1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4 (1·8-5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. Interpretation: Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease. Funding: British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation.

Original language	English
Journal	Lancet
Volume	379
Issue number	9822
Pages (from-to)	1205-13
Number of pages	9
ISSN	0140-6736
DOIs	https://doi.org/10.1016/S0140-6736(11)61931-4
Publication status	Published - 1 Mar 2012

Keywords

Causality
Coronary Disease
Gene Frequency
Genetic Variation
Humans
Inflammation Mediators
Receptors, Interleukin-6
Risk Factors
Signal Transduction

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/S0140-6736(11)61931-4

Cite this

Sarwar, N., Butterworth, A. S., Freitag, D. F., Gregson, J., Willeit, P., Gorman, D. N., Gao, P., Saleheen, D., Rendon, A., Nelson, C. P., Braund, P. S., Hall, A. S., Chasman, D. I., Tybjærg-Hansen, A., Chambers, J. C., Benjamin, E. J., Franks, P. W., Clarke, R., Wilde, A. A. M., ... IL6R Genetics Consortium Emerging Risk Factors Collaboration (2012). Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet, 379(9822), 1205-13. https://doi.org/10.1016/S0140-6736(11)61931-4

Sarwar, N, Butterworth, AS, Freitag, DF, Gregson, J, Willeit, P, Gorman, DN, Gao, P, Saleheen, D, Rendon, A, Nelson, CP, Braund, PS, Hall, AS, Chasman, DI, Tybjærg-Hansen, A, Chambers, JC, Benjamin, EJ, Franks, PW, Clarke, R, Wilde, AAM, Trip, MD, Steri, M, Witteman, JCM, Qi, L, van der Schoot, CE, de Faire, U, Erdmann, J, Stringham, HM, Koenig, W, Rader, DJ, Melzer, D, Reich, D, Psaty, BM, Kleber, ME, Panagiotakos, DB, Willeit, J, Wennberg, P, Woodward, M, Adamovic, S, Rimm, EB, Meade, TW, Gillum, RF, Shaffer, JA, Hofman, A, Onat, A, Sundström, J, Wassertheil-Smoller, S, Mellström, D, Gallacher, J, Allin, KH , Nordestgaard, BG & IL6R Genetics Consortium Emerging Risk Factors Collaboration 2012, 'Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies', Lancet, vol. 379, no. 9822, pp. 1205-13. https://doi.org/10.1016/S0140-6736(11)61931-4

@article{5d942aeae0f6415da8517b18b5a52e0a,

title = "Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies",

abstract = "Background: Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. Methods: In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. Findings: The minor allele frequency of Asp358Ala was 39. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3 (95 CI 30·4-38·2) and of interleukin 6 by 14·6 (10·7-18·4), and mean concentration of C-reactive protein was reduced by 7·5 (5·9-9·1) and of fibrinogen by 1·0 (0·7-1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4 (1·8-5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. Interpretation: Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease. Funding: British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation.",

keywords = "Causality, Coronary Disease, Gene Frequency, Genetic Variation, Humans, Inflammation Mediators, Receptors, Interleukin-6, Risk Factors, Signal Transduction",

author = "Nadeem Sarwar and Butterworth, {Adam S} and Freitag, {Daniel F} and John Gregson and Peter Willeit and Gorman, {Donal N} and Pei Gao and Danish Saleheen and Augusto Rendon and Nelson, {Christopher P} and Braund, {Peter S} and Hall, {Alistair S} and Chasman, {Daniel I} and Anne Tybj{\ae}rg-Hansen and Chambers, {John C} and Benjamin, {Emelia J} and Franks, {Paul W} and Robert Clarke and Wilde, {Arthur A M} and Trip, {Mieke D} and Maristella Steri and Witteman, {Jacqueline C M} and Lu Qi and {van der Schoot}, {C Ellen} and {de Faire}, Ulf and Jeanette Erdmann and Stringham, {Heather M} and Wolfgang Koenig and Rader, {Daniel J} and David Melzer and David Reich and Psaty, {Bruce M} and Kleber, {Marcus E} and Panagiotakos, {Demosthenes B} and Johann Willeit and Patrik Wennberg and Mark Woodward and Svetlana Adamovic and Rimm, {Eric B} and Meade, {Tom W} and Gillum, {Richard F} and Shaffer, {Jonathan A} and Albert Hofman and Altan Onat and Johan Sundstr{\"o}m and Sylvia Wassertheil-Smoller and Dan Mellstr{\"o}m and John Gallacher and Allin, {Kristine H{\o}jgaard} and Nordestgaard, {B{\o}rge G} and {IL6R Genetics Consortium Emerging Risk Factors Collaboration}",

year = "2012",

month = mar,

day = "1",

doi = "10.1016/S0140-6736(11)61931-4",

language = "English",

volume = "379",

pages = "1205--13",

journal = "Lancet",

issn = "0140-6736",

publisher = "TheLancet Publishing Group",

number = "9822",

}

TY - JOUR

T1 - Interleukin-6 receptor pathways in coronary heart disease

T2 - a collaborative meta-analysis of 82 studies

AU - Sarwar, Nadeem

AU - Butterworth, Adam S

AU - Freitag, Daniel F

AU - Gregson, John

AU - Willeit, Peter

AU - Gorman, Donal N

AU - Gao, Pei

AU - Saleheen, Danish

AU - Rendon, Augusto

AU - Nelson, Christopher P

AU - Braund, Peter S

AU - Hall, Alistair S

AU - Chasman, Daniel I

AU - Tybjærg-Hansen, Anne

AU - Chambers, John C

AU - Benjamin, Emelia J

AU - Franks, Paul W

AU - Clarke, Robert

AU - Wilde, Arthur A M

AU - Trip, Mieke D

AU - Steri, Maristella

AU - Witteman, Jacqueline C M

AU - Qi, Lu

AU - van der Schoot, C Ellen

AU - de Faire, Ulf

AU - Erdmann, Jeanette

AU - Stringham, Heather M

AU - Koenig, Wolfgang

AU - Rader, Daniel J

AU - Melzer, David

AU - Reich, David

AU - Psaty, Bruce M

AU - Kleber, Marcus E

AU - Panagiotakos, Demosthenes B

AU - Willeit, Johann

AU - Wennberg, Patrik

AU - Woodward, Mark

AU - Adamovic, Svetlana

AU - Rimm, Eric B

AU - Meade, Tom W

AU - Gillum, Richard F

AU - Shaffer, Jonathan A

AU - Hofman, Albert

AU - Onat, Altan

AU - Sundström, Johan

AU - Wassertheil-Smoller, Sylvia

AU - Mellström, Dan

AU - Gallacher, John

AU - Allin, Kristine Højgaard

AU - Nordestgaard, Børge G

AU - IL6R Genetics Consortium Emerging Risk Factors Collaboration

PY - 2012/3/1

Y1 - 2012/3/1

N2 - Background: Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. Methods: In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. Findings: The minor allele frequency of Asp358Ala was 39. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3 (95 CI 30·4-38·2) and of interleukin 6 by 14·6 (10·7-18·4), and mean concentration of C-reactive protein was reduced by 7·5 (5·9-9·1) and of fibrinogen by 1·0 (0·7-1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4 (1·8-5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. Interpretation: Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease. Funding: British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation.

AB - Background: Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. Methods: In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. Findings: The minor allele frequency of Asp358Ala was 39. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3 (95 CI 30·4-38·2) and of interleukin 6 by 14·6 (10·7-18·4), and mean concentration of C-reactive protein was reduced by 7·5 (5·9-9·1) and of fibrinogen by 1·0 (0·7-1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4 (1·8-5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. Interpretation: Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease. Funding: British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation.

KW - Causality

KW - Coronary Disease

KW - Gene Frequency

KW - Genetic Variation

KW - Humans

KW - Inflammation Mediators

KW - Receptors, Interleukin-6

KW - Risk Factors

KW - Signal Transduction

U2 - 10.1016/S0140-6736(11)61931-4

DO - 10.1016/S0140-6736(11)61931-4

M3 - Journal article

C2 - 22421339

SN - 0140-6736

VL - 379

SP - 1205

EP - 1213

JO - Lancet

JF - Lancet

IS - 9822

ER -

Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies

Abstract

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this