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, 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 - 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 - Kastelein, John J. P.
AU - AUTHOR GROUP
AU - Motazacker, Mahdi
AU - de Jong, Jonas S. S. G.
AU - Dekker, Lucas R. C.
AU - Tanck, Michael
AU - Bezzina, Connie R.
PY - 2012
Y1 - 2012
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
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
U2 - https://doi.org/10.1016/S0140-6736(11)61931-4
DO - https://doi.org/10.1016/S0140-6736(11)61931-4
M3 - Article
C2 - 22421339
SN - 0140-6736
VL - 379
SP - 1205
EP - 1213
JO - Lancet
JF - Lancet
IS - 9822
ER -