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

被引：645

作者：

Sarwar, Nadeem ^{[1
]}

Butterworth, Adam S.

Freitag, Daniel F.

Gregson, John

Willeit, Peter

Gorman, Donal N.

Gao, Pei

Saleheen, Danish

Rendon, Augusto

Nelson, Christopher P. ^{[2
]}

Braund, Peter S. ^{[2
]}

Hall, Alistair S. ^{[3
]}

Chasman, Daniel I. ^{[4
,5
]}

Tybjaerg-Hansen, Anne ^{[6
]}

Chambers, John C.

Benjamin, Emelia J. ^{[8
,9
]}

Franks, Paul W. ^{[10
,11
,12
]}

Clarke, Robert ^{[13
]}

Wilde, Arthur A. M. ^{[14
]}

Trip, Mieke D. ^{[14
]}

Steri, Maristella ^{[15
]}

Witteman, Jacqueline C. M. ^{[16
]}

Qi, Lu ^{[17
]}

van der Schoot, C. Ellen

de Faire, Ulf ^{[18
]}

Erdmann, Jeanette ^{[19
]}

Stringham, Heather M. ^{[20
]}

Koenig, Wolfgang ^{[21
]}

Rader, Daniel J. ^{[22
]}

Melzer, David ^{[23
]}

Reich, David ^{[5
]}

Psaty, Bruce M. ^{[24
]}

Kleber, Marcus E. ^{[25
]}

Panagiotakos, Demosthenes B. ^{[26
]}

Willeit, Johann ^{[27
]}

Wennberg, Patrik

Woodward, Mark ^{[28
]}

Adamovic, Svetlana ^{[29
]}

Rimm, Eric B.

Meade, Tom W. ^{[30
]}

Gillum, Richard F. ^{[31
]}

Shaffer, Jonathan A. ^{[32
]}

Hofman, Albert ^{[16
]}

Onat, Altan ^{[33
]}

Sundstrom, Johan ^{[34
]}

Wassertheil-Smoller, Sylvia ^{[35
]}

Mellstrom, Dan ^{[29
]}

Gallacher, John ^{[36
]}

Cushman, Mary ^{[37
]}

Tracy, Russell P. ^{[37
]}

机构：

[1] Univ Cambridge, Dept Publ Hlth & Primary Care, Strangeways Res Lab, Cambridge CB1 8RN, England

[2] Univ Leicester, Leicester LE1 7RH, Leics, England

[3] Univ Leeds, Leeds LS2 9JT, W Yorkshire, England

[4] Brigham & Womens Hosp, Boston, MA 02115 USA

[5] Harvard Univ, Sch Med, Cambridge, MA 02138 USA

[6] Univ Copenhagen, Copenhagen Univ Hosp, DK-1168 Copenhagen, Denmark

[7] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London SW7 2AZ, England

[8] Boston Univ, Sch Med & Publ Hlth, Boston, MA 02215 USA

[9] NHLBI, Framingham Heart Study, Framingham, MA USA

[10] Lund Univ, Skane Univ Hosp, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden

[11] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA

[12] Umea Univ, Dept Publ Hlth & Clin Med, Med Sect, Umea, Sweden

[13] Univ Oxford, Oxford OX1 2JD, England

[14] Univ Amsterdam, Acad Med Ctr, NL-1012 WX Amsterdam, Netherlands

[15] CNR, IRGB, I-00185 Rome, Italy

[16] Erasmus MC, Rotterdam, Netherlands

[17] Harvard Univ, Sch Publ Hlth, Brigham & Womens Hosp, Cambridge, MA 02138 USA

[18] Karolinska Inst, S-10401 Stockholm, Sweden

[19] Univ Lubeck, Lubeck, Germany

[20] Univ Michigan, Ann Arbor, MI 48109 USA

[21] Univ Ulm, D-89069 Ulm, Germany

[22] Univ Penn, Philadelphia, PA 19104 USA

[23] Univ Exeter, Peninsula Coll Med & Dent, Exeter EX4 4QJ, Devon, England

[24] Univ Washington, Seattle, WA 98195 USA

[25] LURIC Study Nonprofit LLC, Freiburg, Germany

[26] Harokopio Univ Athens, Athens, Greece

[27] Med Univ Innsbruck, Innsbruck, Austria

[28] Univ Sydney, Sydney, NSW 2006, Australia

[29] Sahlgrens Univ Hosp, Gothenburg, Sweden

[30] London Sch Hyg & Trop Med, London, England

[31] Ctr Dis Control & Prevent, Atlanta, GA USA

[32] Columbia Univ, Med Ctr, New York, NY 10027 USA

[33] Istanbul Univ, Istanbul, Turkey

[34] Uppsala Univ, Uppsala, Sweden

[35] Albert Einstein Coll Med, Bronx, NY USA

[36] Cardiff Univ, Cardiff, Wales

[37] Univ Vermont, Burlington, VT 05405 USA

[38] Univ Eastern Finland, Kuopio, Finland

[39] Lund Univ, S-22100 Lund, Sweden

[40] Univ Gothenburg, Gothenburg, Sweden

[41] Inst Pasteur, Lille, France

[42] Hop Laval, Laval, PQ, Canada

[43] Missouri Breaks Ind Res Inc, Timber Lake, MO USA

[44] Univ Bristol, Bristol BS8 1TH, Avon, England

[45] Univ Edinburgh, Edinburgh EH8 9YL, Midlothian, Scotland

[46] Univ Sheffield, Sheffield S10 2TN, S Yorkshire, England

[47] Stanford Univ, Sch Med, Stanford, CA 94305 USA

[48] Gothenburg Univ, S-41124 Gothenburg, Sweden

[49] Uppsala Univ, S-75105 Uppsala, Sweden

[50] Karolinska Inst, Stockholm, Sweden

来源：

LANCET | 2012年 / 379卷 / 9822期

基金：

英国医学研究理事会;

关键词：

C-REACTIVE PROTEIN; RHEUMATOID-ARTHRITIS; RISK; LOCI; ASSOCIATION; TOCILIZUMAB; FIBRINOGEN; INFLAMMATION; INHIBITION; REDUCTION;

D O I：

10.1016/S0140-6736(11)61931-4

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：1205 / 1213

页数：9

共 49 条

[1] Cardiovascular Biology of Interleukin-6 [J].

Abeywardena, Mahinda Y. ;

Leifert, Wayne R. ;

Warnes, Kirsty E. ;

Varghese, Jose N. ;

Head, Richard J. .

CURRENT PHARMACEUTICAL DESIGN, 2009, 15 (15) :1809-1821

[2]

[Anonymous], ICHG ASHG SCI M MONT

[3]

[Anonymous], FDA APPR NEW DRUG RH

[4] Clinical safety of tocilizumab in rheumatoid arthritis [J].

Bannwarth, Bernard ;

Richez, Christophe .

EXPERT OPINION ON DRUG SAFETY, 2011, 10 (01) :123-131

[5] Large-Scale Gene-Centric Analysis Identifies Novel Variants for Coronary Artery Disease [J].

Butterworth, Adam S. ;

Braund, Peter S. ;

Farrall, Martin ;

Hardwick, Robert J. ;

Saleheen, Danish ;

Peden, John F. ;

Soranzo, Nicole ;

Chambers, John C. ;

Sivapalaratnam, Suthesh ;

Kleber, Marcus E. ;

Keating, Brendan ;

Qasim, Atif ;

Klopp, Norman ;

Erdmann, Jeanette ;

Assimes, Themistocles L. ;

Ball, Stephen G. ;

Balmforth, Anthony J. ;

Barnes, Timothy A. ;

Basart, Hanneke ;

Baumert, Jens ;

Bezzina, Connie R. ;

Boerwinkle, Eric ;

Boehm, Bernhard O. ;

Brocheton, Jessy ;

Bugert, Peter ;

Cambien, Francois ;

Clarke, Robert ;

Codd, Veryan ;

Collins, Rory ;

Couper, David ;

Cupples, L. Adrienne ;

de Jong, Jonas S. ;

Diemert, Patrick ;

Ejebe, Kenechi ;

Elbers, Clara C. ;

Elliott, Paul ;

Fornage, Myriam ;

Franzosi, Maria-Grazia ;

Frossard, Philippe ;

Garner, Stephen ;

Goel, Anuj ;

Goodall, Alison H. ;

Hengstenberg, Christian ;

Hunt, Sarah E. ;

Kastelein, John J. P. ;

Klungel, Olaf H. ;

Klueter, Harald ;

Koch, Kerstin ;

Koenig, Inke R. ;

Kooner, Angad S. .

PLOS GENETICS, 2011, 7 (09)

[6] Interpreting lipid levels in the context of high-grade inflammatory states with a focus on rheumatoid arthritis: a challenge to conventional cardiovascular risk actions [J].

Choy, E. ;

Sattar, N. .

ANNALS OF THE RHEUMATIC DISEASES, 2009, 68 (04) :460-469

[7] Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality - An individual participant meta-analysis [J].

Danesh, J ;

Lewington, S ;

Thompson, SG ;

Lowe, GDO ;

Collins, R .

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2005, 294 (14) :1799-1809

[8] Long-term interleukin-6 levels and subsequent risk of coronary heart disease: Two new prospective studies and a systematic review [J].

Danesh, John ;

Kaptoge, Stephen ;

Mann, Andrea G. ;

Sarwar, Nadeem ;

Wood, Angela ;

Angleman, Sara B. ;

Wensley, Frances ;

Higgins, Julian P. T. ;

Lennon, Lucy ;

Eiriksdottir, Gudny ;

Rumley, Ann ;

Whincup, Peter H. ;

Lowe, Gordon D. O. ;

Gudnason, Vilmundur .

PLOS MEDICINE, 2008, 5 (04) :600-610

[9] Novel Loci, Including Those Related to Crohn Disease, Psoriasis, and Inflammation, Identified in a Genome-Wide Association Study of Fibrinogen in 17 686 Women The Women's Genome Health Study [J].

Danik, Jacqueline S. ;

Pare, Guillaume ;

Chasman, Daniel I. ;

Zee, Robert Y. L. ;

Kwiatkowski, David J. ;

Parker, Alex ;

Miletich, Joseph P. ;

Ridker, Paul M. .

CIRCULATION-CARDIOVASCULAR GENETICS, 2009, 2 (02) :134-141

[10] Meta-Analysis of Genome-Wide Association Studies in >80 000 Subjects Identifies Multiple Loci for C-Reactive Protein Levels [J].

Dehghan, Abbas ;

Dupuis, Josee ;

Barbalic, Maja ;

Bis, Joshua C. ;

Eiriksdottir, Gudny ;

Lu, Chen ;

Pellikka, Niina ;

Wallaschofski, Henri ;

Kettunen, Johannes ;

Henneman, Peter ;

Baumert, Jens ;

Strachan, David P. ;

Fuchsberger, Christian ;

Vitart, Veronique ;

Wilson, James F. ;

Pare, Guillaume ;

Naitza, Silvia ;

Rudock, Megan E. ;

Surakka, Ida ;

de Geus, Eco J. C. ;

Alizadeh, Behrooz Z. ;

Guralnik, Jack ;

Shuldiner, Alan ;

Tanaka, Toshiko ;

Zee, Robert Y. L. ;

Schnabel, Renate B. ;

Nambi, Vijay ;

Kavousi, Maryam ;

Ripatti, Samuli ;

Nauck, Matthias ;

Smith, Nicholas L. ;

Smith, Albert V. ;

Sundvall, Jouko ;

Scheet, Paul ;

Liu, Yongmei ;

Ruokonen, Aimo ;

Rose, Lynda M. ;

Larson, Martin G. ;

Hoogeveen, Ron C. ;

Freimer, Nelson B. ;

Teumer, Alexander ;

Tracy, Russell P. ;

Launer, Lenore J. ;

Buring, Julie E. ;

Yamamoto, Jennifer F. ;

Folsom, Aaron R. ;

Sijbrands, Eric J. G. ;

Pankow, James ;

Elliott, Paul ;

Keaney, John F. .

CIRCULATION, 2011, 123 (07) :731-U151

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