TY - JOUR
AU - Gao P.
AU - Psaty B.
AU - Asselbergs F.
AU - Sarwar N.
AU - Butterworth A.
AU - Freitag D.
AU - Gregson J.
AU - Willeit P.
AU - Gorman D.
AU - Saleheen D.
AU - Rendon A.
AU - Nelson C.
AU - Braund P.
AU - Hall A.
AU - Chasman D.
AU - Tybjaerg-Hansen A.
AU - Chambers J.
AU - Benjamin E.
AU - Franks P.
AU - Clarke R.
AU - Wilde A.
AU - Trip M.
AU - Steri M.
AU - Witteman J.
AU - Qi L.
AU - van der Schoot C.
AU - de Faire U.
AU - Erdmann J.
AU - Stringham H.
AU - Koenig W.
AU - Rader D.
AU - Melzer D.
AU - Reich D.
AU - Kleber M.
AU - Panagiotakos D.
AU - Willeit J.
AU - Wennberg P.
AU - Adamovic S.
AU - Rimm E.
AU - Meade T.
AU - Gillum R.
AU - Shaffer J.
AU - Hofman A.
AU - Onat A.
AU - Sundstrom J.
AU - Wassertheil-Smoller S.
AU - Mellstrom D.
AU - Gallacher J.
AU - Cushman M.
AU - Tracy R.
AU - Kauhanen J.
AU - Karlsson M.
AU - Salonen J.
AU - Wilhelmsen L.
AU - Amouyel P.
AU - Cantin B.
AU - Best L.
AU - Ben-Shlomo Y.
AU - Manson J.
AU - Davey-Smith G.
AU - de Bakker P.
AU - O'Donnell C.
AU - Wilson J.
AU - Wilson A.
AU - Assimes T.
AU - Jansson J.
AU - Ohlsson C.
AU - Tivesten A.
AU - Ljunggren O.
AU - Reilly M.
AU - Hamsten A.
AU - Ingelsson E.
AU - Hung J.
AU - Thomas G.
AU - Boehnke M.
AU - Schunkert H.
AU - Kastelein J.
AU - Gudnason V.
AU - Salomaa V.
AU - Harris T.
AU - Kooner J.
AU - Allin K.
AU - Nordestgaard B.
AU - Hopewell J.
AU - Goodall A.
AU - Ridker P.
AU - Holm H.
AU - Watkins H.
AU - Ouwehand W.
AU - Samani N.
AU - Kaptoge S.
AU - Di Angelantonio E.
AU - Harari O.
AU - Danesh J.
AU - Woodward Mark
AU - IL6R Genetics Consortium Emerging Risk Factors Collaboration
AU - Cambien F.
AB - <p>
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 &gt;/=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.
</p>

AN - 22421339
BT - Lancet
C2 - 3316940
DA - 204106444252
DP - NLM
ET - 2012/03/17
LA - eng
M1 - 9822
N1 - IL6R Genetics Consortium Emerging Risk Factors CollaborationSarwar, NadeemButterworth, Adam SFreitag, Daniel FGregson, JohnWilleit, PeterGorman, Donal NGao, PeiSaleheen, DanishRendon, AugustoNelson, Christopher PBraund, Peter SHall, Alistair SChasman, Daniel ITybjaerg-Hansen, AnneChambers, John CBenjamin, Emelia JFranks, Paul WClarke, RobertWilde, Arthur A MTrip, Mieke DSteri, MaristellaWitteman, Jacqueline C MQi, Luvan der Schoot, C Ellende Faire, UlfErdmann, JeanetteStringham, Heather MKoenig, WolfgangRader, Daniel JMelzer, DavidReich, DavidPsaty, Bruce MKleber, Marcus EPanagiotakos, Demosthenes BWilleit, JohannWennberg, PatrikWoodward, MarkAdamovic, SvetlanaRimm, Eric BMeade, Tom WGillum, Richard FShaffer, Jonathan AHofman, AlbertOnat, AltanSundstrom, JohanWassertheil-Smoller, SylviaMellstrom, DanGallacher, JohnCushman, MaryTracy, Russell PKauhanen, JussiKarlsson, MagnusSalonen, Jukka TWilhelmsen, LarsAmouyel, PhilippeCantin, BernardBest, Lyle GBen-Shlomo, YoavManson, JoAnn EDavey-Smith, Georgede Bakker, Paul I WO'Donnell, Christopher JWilson, James FWilson, Anthony GAssimes, Themistocles LJansson, John-OlovOhlsson, ClaesTivesten, AsaLjunggren, OstenReilly, Muredach PHamsten, AndersIngelsson, ErikCambien, FrancoisHung, JosephThomas, G NeilBoehnke, MichaelSchunkert, HeribertAsselbergs, Folkert WKastelein, John J PGudnason, VilmundurSalomaa, VeikkoHarris, Tamara BKooner, Jaspal SAllin, Kristine HNordestgaard, Borge GHopewell, Jemma CGoodall, Alison HRidker, Paul MHolm, HilmaWatkins, HughOuwehand, Willem HSamani, Nilesh JKaptoge, StephenDi Angelantonio, EmanueleHarari, OlivierDanesh, JohnRG/08/014/British Heart Foundation/United KingdomMedical Research Council/United KingdomMeta-AnalysisResearch Support, Non-U.S. Gov'tEnglandLancet. 2012 Mar 31;379(9822):1205-13. Epub 2012 Mar 14.
N2 - <p>
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 &gt;/=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.
</p>

PY - 2012
SN - 1474-547X (Electronic)0140-6736 (Linking)
SP - 1205
EP - 13
T2 - Lancet
TI - Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies
VL - 379
ER -