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Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies.
Lancet 2012; 379(9822):1205-13Lct

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.

Authors

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Pub Type(s)

Journal Article
Meta-Analysis
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22421339

Citation

IL6R Genetics Consortium Emerging Risk Factors Collaboration, et al. "Interleukin-6 Receptor Pathways in Coronary Heart Disease: a Collaborative Meta-analysis of 82 Studies." Lancet (London, England), vol. 379, no. 9822, 2012, pp. 1205-13.
IL6R Genetics Consortium Emerging Risk Factors Collaboration, Sarwar N, Butterworth AS, et al. Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet. 2012;379(9822):1205-13.
Sarwar, N., Butterworth, A. S., Freitag, D. F., Gregson, J., Willeit, P., Gorman, D. N., ... Danesh, J. (2012). Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet (London, England), 379(9822), pp. 1205-13. doi:10.1016/S0140-6736(11)61931-4.
IL6R Genetics Consortium Emerging Risk Factors Collaboration, et al. Interleukin-6 Receptor Pathways in Coronary Heart Disease: a Collaborative Meta-analysis of 82 Studies. Lancet. 2012 Mar 31;379(9822):1205-13. PubMed PMID: 22421339.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. AU - ,, 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 - Cushman,Mary, AU - Tracy,Russell P, AU - Kauhanen,Jussi, AU - Karlsson,Magnus, AU - Salonen,Jukka T, AU - Wilhelmsen,Lars, AU - Amouyel,Philippe, AU - Cantin,Bernard, AU - Best,Lyle G, AU - Ben-Shlomo,Yoav, AU - Manson,JoAnn E, AU - Davey-Smith,George, AU - de Bakker,Paul I W, AU - O'Donnell,Christopher J, AU - Wilson,James F, AU - Wilson,Anthony G, AU - Assimes,Themistocles L, AU - Jansson,John-Olov, AU - Ohlsson,Claes, AU - Tivesten,Åsa, AU - Ljunggren,Östen, AU - Reilly,Muredach P, AU - Hamsten,Anders, AU - Ingelsson,Erik, AU - Cambien,Francois, AU - Hung,Joseph, AU - Thomas,G Neil, AU - Boehnke,Michael, AU - Schunkert,Heribert, AU - Asselbergs,Folkert W, AU - Kastelein,John J P, AU - Gudnason,Vilmundur, AU - Salomaa,Veikko, AU - Harris,Tamara B, AU - Kooner,Jaspal S, AU - Allin,Kristine H, AU - Nordestgaard,Børge G, AU - Hopewell,Jemma C, AU - Goodall,Alison H, AU - Ridker,Paul M, AU - Hólm,Hilma, AU - Watkins,Hugh, AU - Ouwehand,Willem H, AU - Samani,Nilesh J, AU - Kaptoge,Stephen, AU - Di Angelantonio,Emanuele, AU - Harari,Olivier, AU - Danesh,John, Y1 - 2012/03/14/ PY - 2012/3/17/entrez PY - 2012/3/17/pubmed PY - 2012/4/11/medline SP - 1205 EP - 13 JF - Lancet (London, England) JO - Lancet VL - 379 IS - 9822 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. SN - 1474-547X UR - https://www.unboundmedicine.com/medline/citation/22421339/full_citation L2 - https://linkinghub.elsevier.com/retrieve/pii/S0140-6736(11)61931-4 DB - PRIME DP - Unbound Medicine ER -