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

Nadeem Sarwar; Adam S. Butterworth; D. F. Freitag; J. Gregson; P. Willeit; D. N. Gorman; P. Gao; D. Saleheen; A. Rendon; C. P. Nelson; P. S. Braund; A. S. Hall; D. I. Chasman; A. Tybjærg-Hansen; J. C. Chambers; E. J. Benjamin; P. W. Franks; R. Clarke; A. A. Wilde; M. D. Trip; M. Steri; J. C. Witteman; L. Qi; C. E. van der Schoot; U. de Faire; J. Erdmann; H. M. Stringham; W. Koenig; D. J. Rader; D. Melzer; D. Reich; B. M. Psaty; M. E. Kleber; D. B. Panagiotakos; J. Willeit; P. Wennberg; M. Woodward; S. Adamovic; E. B. Rimm; T. W. Meade; R. F. Gillum; J. A. Shaffer; A. Hofman; A. Onat; J. Sundström; S. Wassertheil-Smoller; D. Mellström; H. Schunkert; Christina Willenborg; Members of the IL6R Genetics Consortium and the Emerging Risk Factors Collaboration; Michael Preuss

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, D. F. Freitag, J. Gregson, P. Willeit, D. N. Gorman, P. Gao, D. Saleheen, A. Rendon, C. P. Nelson, P. S. Braund, A. S. Hall, D. I. Chasman, A. Tybjærg-Hansen, J. C. Chambers, E. J. Benjamin, P. W. Franks, R. Clarke, A. A. Wilde, M. D. TripM. Steri, J. C. Witteman, L. Qi, C. E. van der Schoot, U. de Faire, J. Erdmann, H. M. Stringham, W. Koenig, D. J. Rader, D. Melzer, D. Reich, B. M. Psaty, M. E. Kleber, D. B. Panagiotakos, J. Willeit, P. Wennberg, M. Woodward, S. Adamovic, E. B. Rimm, T. W. Meade, R. F. Gillum, J. A. Shaffer, A. Hofman, A. Onat, J. Sundström, S. Wassertheil-Smoller, D. Mellström, H. Schunkert, Christina Willenborg, Members of the IL6R Genetics Consortium and the Emerging Risk Factors Collaboration, Michael Preuss

^*Korrespondierende/r Autor/-in für diese Arbeit

University of Cambridge

281 Zitate (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.

Originalsprache	Englisch
Zeitschrift	The Lancet
Jahrgang	379
Ausgabenummer	9822
Seiten (von - bis)	1205-1213
Seitenumfang	9
ISSN	0140-6736
DOIs	https://doi.org/10.1016/S0140-6736(11)61931-4
Publikationsstatus	Veröffentlicht - 01.03.2012

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10.1016/S0140-6736(11)61931-4

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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., ... Preuss, M. (2012). Interleukin-6 receptor pathways in coronary heart disease: A collaborative meta-analysis of 82 studies. The Lancet, 379(9822), 1205-1213. https://doi.org/10.1016/S0140-6736(11)61931-4

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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.",

author = "Nadeem Sarwar and Butterworth, {Adam S.} and Freitag, {D. F.} and J. Gregson and P. Willeit and Gorman, {D. N.} and P. Gao and D. Saleheen and A. Rendon and Nelson, {C. P.} and Braund, {P. S.} and Hall, {A. S.} and Chasman, {D. I.} and A. Tybj{\ae}rg-Hansen and Chambers, {J. C.} and Benjamin, {E. J.} and Franks, {P. W.} and R. Clarke and Wilde, {A. A.} and Trip, {M. D.} and M. Steri and Witteman, {J. C.} and L. Qi and {van der Schoot}, {C. E.} and {de Faire}, U. and J. Erdmann and Stringham, {H. M.} and W. Koenig and Rader, {D. J.} and D. Melzer and D. Reich and Psaty, {B. M.} and Kleber, {M. E.} and Panagiotakos, {D. B.} and J. Willeit and P. Wennberg and M. Woodward and S. Adamovic and Rimm, {E. B.} and Meade, {T. W.} and Gillum, {R. F.} and Shaffer, {J. A.} and A. Hofman and A. Onat and J. Sundstr{\"o}m and S. Wassertheil-Smoller and D. Mellstr{\"o}m and H. Schunkert and Christina Willenborg and {Members of the IL6R Genetics Consortium and the Emerging Risk Factors Collaboration} and Michael Preuss",

year = "2012",

month = mar,

day = "1",

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

language = "English",

volume = "379",

pages = "1205--1213",

journal = "The Lancet",

issn = "0140-6736",

number = "9822",

}

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, AA, Trip, MD, Steri, M, Witteman, JC, 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, Schunkert, H, Willenborg, C, Members of the IL6R Genetics Consortium and the Emerging Risk Factors Collaboration & Preuss, M 2012, 'Interleukin-6 receptor pathways in coronary heart disease: A collaborative meta-analysis of 82 studies', The Lancet, Jg. 379, Nr. 9822, S. 1205-1213. https://doi.org/10.1016/S0140-6736(11)61931-4

TY - JOUR

T1 - Interleukin-6 receptor pathways in coronary heart disease: A collaborative meta-analysis of 82 studies

AU - Sarwar, Nadeem

AU - Butterworth, Adam S.

AU - Freitag, D. F.

AU - Gregson, J.

AU - Willeit, P.

AU - Gorman, D. N.

AU - Gao, P.

AU - Saleheen, D.

AU - Rendon, A.

AU - Nelson, C. P.

AU - Braund, P. S.

AU - Hall, A. S.

AU - Chasman, D. I.

AU - Tybjærg-Hansen, A.

AU - Chambers, J. C.

AU - Benjamin, E. J.

AU - Franks, P. W.

AU - Clarke, R.

AU - Wilde, A. A.

AU - Trip, M. D.

AU - Steri, M.

AU - Witteman, J. C.

AU - Qi, L.

AU - van der Schoot, C. E.

AU - de Faire, U.

AU - Erdmann, J.

AU - Stringham, H. M.

AU - Koenig, W.

AU - Rader, D. J.

AU - Melzer, D.

AU - Reich, D.

AU - Psaty, B. M.

AU - Kleber, M. E.

AU - Panagiotakos, D. B.

AU - Willeit, J.

AU - Wennberg, P.

AU - Woodward, M.

AU - Adamovic, S.

AU - Rimm, E. B.

AU - Meade, T. W.

AU - Gillum, R. F.

AU - Shaffer, J. A.

AU - Hofman, A.

AU - Onat, A.

AU - Sundström, J.

AU - Wassertheil-Smoller, S.

AU - Mellström, D.

AU - Schunkert, H.

AU - Willenborg, Christina

AU - Members of the IL6R Genetics Consortium and the Emerging Risk Factors Collaboration

AU - Preuss, Michael

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.

UR - http://www.scopus.com/inward/record.url?scp=84859210770&partnerID=8YFLogxK

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

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

M3 - Journal articles

AN - SCOPUS:84859210770

SN - 0140-6736

VL - 379

SP - 1205

EP - 1213

JO - The Lancet

JF - The Lancet

IS - 9822

ER -

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

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