@article{63babcfa63bb49af966b82ab63f3f62d,
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 = "{Members of the IL6R Genetics Consortium and the Emerging Risk Factors Collaboration} and 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 J. Gallacher and M. Cushman and Fontes, {Jo{\~a}o D.}",
note = "Funding Information: Paul M Ridker is listed as a co-inventor on patents held by Brigham and Women's Hospital that relate to the use of inflammatory markers in cardiovascular disease, and that have been licensed to AstraZeneca and Siemens. John Danesh has received research funding from the British Heart Foundation, BUPA Foundation, Denka, diaDexus, European Union, European Research Council, Evelyn Trust, Fogarty International Centre, GlaxoSmithKline, Medical Research Council, Merck Sharp and Dohme, National Heart, Lung and Blood Institute, National Institute of Neurological Disorders and Stroke, National Institute for Health Research, Novartis, Pfizer, Roche, Wellcome Trust, and UK Biobank, and has served on advisory boards for Merck, Pfizer, and Novartis, for which he has received compensation. All other members of the writing committee declare that they have no conflicts of interest. Funding Information: The coordinating centre was supported by the British Heart Foundation ( RG/08/014 ), the UK Medical Research Council, the UK National Institute of Health Research, Cambridge Biomedical Research Centre, and a specific grant from the BUPA Foundation. Various sources have supported recruitment, follow-up, and laboratory measurements in the studies contributing to this report. Investigators of several of these studies have contributed to a list naming some of these funding sources . Sekar Kathiresan, Kenneth G C Smith, and John Todd commented helpfully on an earlier version of this report. ",
year = "2012",
month = mar,
day = "1",
doi = "10.1016/S0140-6736(11)61931-4",
language = "English (US)",
volume = "379",
pages = "1205--1213",
journal = "The Lancet",
issn = "0140-6736",
publisher = "Elsevier Limited",
number = "9822",
}