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Lancet. 2012 Mar 31;379(9822):1205-13. doi: 10.1016/S0140-6736(11)61931-4. Epub 2012 Mar 14.

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

Collaborators (229)

Assimes TL, Quertermous T, Go AS, Hlatky MA, Knowles JW, Gudnason V, Smith AV, Panagiotakos DB, Chrysohoou C, Pitsavos C, Stefanadis C, Nelson CP, Braund PS, Samani NJ, Hall AS, Balmforth AJ, Thompson JR, Rendon A, Wilde AA, Trip MD, van der Schoot CE, Kastelein JJ, Ouwehand WH, Sivapalaratnam S, Maiwald S, Basart H, Motazacker M, de Jong JS, Dekker LR, Tanck M, Bezzina CR, Whincup PH, Morris RW, Wannamethee SG, Willeit J, Kiechl S, Gallacher J, Yarnell JW, Lowe G, Rumley A, Samani NJ, Goodall AH, Cambien F, Cushman M, Mukamal KJ, Nordestgaard BG, Tybjærg-Hansen A, Allin KH, Salomaa V, Havulinna AS, Lokki ML, Nieminen MS, Ripatti S, Sinisalo J, Hung J, McQuillan BM, Beilby JP, Thompson PL, Hólm H, Thorleifsson G, Thorgeirsson G, Thorsteinsdóttir U, Stefansson K, Salomaa V, Jula A, Männistö S, Perola M, Tikkanen E, Asselbergs FW, Boer JM, Onland-Moret NC, van der Schouw YT, Verschuren WM, de Bakker PI, Wennberg P, Jansson JH, Salomaa V, Woodward M, Benjamin EJ, Dupuis J, Fontes JD, Yin X, O'Donnell CJ, Boehnke M, Stringham HM, Tuomilehto J, Schunkert H, Erdmann J, Koenig IR, Nahrstaedt J, Loley C, Stark K, Willenborg C, Hengstenberg C, Schreiber S, Preuss M, Franks PW, Barroso I, Hallmans G, Shungin D, Thomas GN, Cheng KK, Lam TH, Jiang CC, Reich D, Harris TB, Rimm EB, Pai J, Hopewell JC, Collins R, Parish S, Armitage J, Stringham HM, Jackson A, Hveem K, Psaty BM, Wiggins KL, Heckbert SR, Smith NL, Bis JC, Melzer D, Ferrucci L, Guralnik JM, Bandinelli S, Singleton AB, Kauhanen J, Salonen JT, Tuomainen TP, Kurl S, Meade TW, Chambers JC, Kooner JS, Zhang W, Kooner AS, Das D, Kleber ME, März W, Scharnagl H, Böhm BO, Winkelmann BR, Cushman M, Tracy RP, Folsom AR, Psaty BM, Shea SJ, Stringham HM, Laakso M, Kuusisto J, Koenig W, Baumert J, Thorand B, Illig T, Meisinger C, Wilhelmsen L, Rosengren A, Jansson JO, Adamovic S, Karlsson MK, Ljunggren Ö, Mellström D, Ohlsson C, Tivesten Å, Gillum RF, Rimm EB, Manson JE, Qi L, Hu FB, Hankinson SE, Shaffer JA, Davidson KW, Wilson JF, Fraser R, Wild S, Campbell H, Rader DJ, Reilly MP, Qasim A, Qu L, Li M, Ingelsson E, Lind L, Sundström J, Syvänen AC, Amouyel P, Arveiler D, Clarke R, Watkins H, Farrall M, Hopewell JC, Peden JF, Saleheen D, Deloukas P, Sheikh N, Rasheed A, Danesh J, Cantin B, Dagenais GR, Witteman JC, Hofman A, Dehghan A, van Duijn CM, Uitterlinden AG, Steri M, Abecasis GR, Cucca F, Sanna S, Uda M, Schlessinger D, Hamsten A, Sabater-Lleal M, Silveira A, de Faire U, Gigante B, Best LG, Howard BV, Davey-Smith G, Ben-Shlomo Y, Onat A, Ingelsson E, Sundström J, Lind L, Basu S, Syvänen AC, Ridker PM, Chasman DI, Rose LM, Wassertheil-Smoller S, Ridker PM, Buring J.

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.

Copyright © 2012 Elsevier Ltd. All rights reserved.

Comment in

PMID:
22421339
[PubMed - indexed for MEDLINE]
PMCID:
PMC3316940
Free PMC Article

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