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

N Sarwar; AS Butterworth; DF Freitag; J Gregson; P Willeit; DN Gorman; P Gao; D Saleheen; A Rendon; CP Nelson; PS Braund; AS Hall; DI Chasman; A Tybjaerg-Hansen; JC Chambers; EJ Benjamin; PW Franks; R Clarke; AAM Wilde; MD Trip; M Steri; JCM Witteman; L Qi; CE van der Schoot; U de Faire; J Erdmann; HM Stringham; W Koenig; DJ Rader; D Melzer; D Reich; BM Psaty; ME Kleber; DB Panagiotakos; J Willeit; P Wennberg; M Woodward; S Adamovic; EB Rimm; TW Meade; RF Gillum; JA Shaffer; Bert Hofman; A Onat; J Sundstrom; S Wassertheil-Smoller; D Mellstrom; J Gallacher; M Cushman; RP Tracy; J Kauhanen; M Karlsson; JT Salonen; L Wilhelmsen; P Amouyel; B Cantin; LG Best; Y Ben-Shlomo; JE Manson; G Davey-Smith; PIW de Bakker; CJ O'Donnell; JF Wilson; AG Wilson; TL Assimes; JO Jansson; C Ohlsson; A Tivesten; O Ljunggren; MP Reilly; A Hamsten; E Ingelsson; F Cambien; J Hung; GN Thomas; M Boehnke; H Schunkert; FW Asselbergs; JJP Kastelein; V Gudnason; V Salomaa; TB Harris; JS Kooner; KH Allin; BG Nordestgaard; JC Hopewell; AH Goodall; PM Ridker; H Holm; H Watkins; WH Ouwehand; NJ Samani; S Kaptoge; E Di Angelantonio; O Harari; J Danesh

doi:10.1016/S0140-6736(11)61931-4

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

N Sarwar, AS Butterworth, DF Freitag, J Gregson, P Willeit, DN Gorman, P Gao, D Saleheen, A Rendon, CP Nelson, PS Braund, AS Hall, DI Chasman, A Tybjaerg-Hansen, JC Chambers, EJ Benjamin, PW Franks, R Clarke, AAM Wilde, MD TripM Steri, JCM Witteman, L Qi, CE van der Schoot, U de Faire, J Erdmann, HM Stringham, W Koenig, DJ Rader, D Melzer, D Reich, BM Psaty, ME Kleber, DB Panagiotakos, J Willeit, P Wennberg, M Woodward, S Adamovic, EB Rimm, TW Meade, RF Gillum, JA Shaffer, Bert Hofman, A Onat, J Sundstrom, S Wassertheil-Smoller, D Mellstrom, J Gallacher, M Cushman, RP Tracy, J Kauhanen, M Karlsson, JT Salonen, L Wilhelmsen, P Amouyel, B Cantin, LG Best, Y Ben-Shlomo, JE Manson, G Davey-Smith, PIW de Bakker, CJ O'Donnell, JF Wilson, AG Wilson, TL Assimes, JO Jansson, C Ohlsson, A Tivesten, O Ljunggren, MP Reilly, A Hamsten, E Ingelsson, F Cambien, J Hung, GN Thomas, M Boehnke, H Schunkert, FW Asselbergs, JJP Kastelein, V Gudnason, V Salomaa, TB Harris, JS Kooner, KH Allin, BG Nordestgaard, JC Hopewell, AH Goodall, PM Ridker, H Holm, H Watkins, WH Ouwehand, NJ Samani, S Kaptoge, E Di Angelantonio, O Harari, J Danesh

Epidemiology

Research output: Contribution to journal › Article › Academic › peer-review

671 Citations (Scopus)

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 Interpretation Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease.

Original language	Undefined/Unknown
Pages (from-to)	1205-1213
Number of pages	9
Journal	Lancet (UK)
Volume	379
Issue number	9822
DOIs	https://doi.org/10.1016/S0140-6736(11)61931-4
Publication status	Published - 2012

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EMC COEUR-09
EMC NIHES-01-64-01
EMC NIHES-01-64-02

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10.1016/S0140-6736(11)61931-4

Cite this

Sarwar, N., Butterworth, AS., Freitag, DF., Gregson, J., Willeit, P., Gorman, DN., Gao, P., Saleheen, D., Rendon, A., Nelson, CP., Braund, PS., Hall, AS., Chasman, DI., Tybjaerg-Hansen, A., Chambers, JC., Benjamin, EJ., Franks, PW., Clarke, R., Wilde, AAM., ... Danesh, J. (2012). Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet (UK), 379(9822), 1205-1213. https://doi.org/10.1016/S0140-6736(11)61931-4

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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 Interpretation Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease.",

author = "N Sarwar and AS Butterworth and DF Freitag and J Gregson and P Willeit and DN Gorman and P Gao and D Saleheen and A Rendon and CP Nelson and PS Braund and AS Hall and DI Chasman and A Tybjaerg-Hansen and JC Chambers and EJ Benjamin and PW Franks and R Clarke and AAM Wilde and MD Trip and M Steri and JCM Witteman and L Qi and {van der Schoot}, CE and {de Faire}, U and J Erdmann and HM Stringham and W Koenig and DJ Rader and D Melzer and D Reich and BM Psaty and ME Kleber and DB Panagiotakos and J Willeit and P Wennberg and M Woodward and S Adamovic and EB Rimm and TW Meade and RF Gillum and JA Shaffer and Bert Hofman and A Onat and J Sundstrom and S Wassertheil-Smoller and D Mellstrom and J Gallacher and M Cushman and RP Tracy and J Kauhanen and M Karlsson and JT Salonen and L Wilhelmsen and P Amouyel and B Cantin and LG Best and Y Ben-Shlomo and JE Manson and G Davey-Smith and {de Bakker}, PIW and CJ O'Donnell and JF Wilson and AG Wilson and TL Assimes and JO Jansson and C Ohlsson and A Tivesten and O Ljunggren and MP Reilly and A Hamsten and E Ingelsson and F Cambien and J Hung and GN Thomas and M Boehnke and H Schunkert and FW Asselbergs and JJP Kastelein and V Gudnason and V Salomaa and TB Harris and JS Kooner and KH Allin and BG Nordestgaard and JC Hopewell and AH Goodall and PM Ridker and H Holm and H Watkins and WH Ouwehand and NJ Samani and S Kaptoge and {Di Angelantonio}, E and O Harari and J Danesh",

year = "2012",

doi = "10.1016/S0140-6736(11)61931-4",

language = "Undefined/Unknown",

volume = "379",

pages = "1205--1213",

journal = "Lancet (UK)",

issn = "0140-6736",

publisher = "Elsevier",

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Sarwar, N, Butterworth, AS, Freitag, DF, Gregson, J, Willeit, P, Gorman, DN, Gao, P, Saleheen, D, Rendon, A, Nelson, CP, Braund, PS, Hall, AS, Chasman, DI, Tybjaerg-Hansen, A, Chambers, JC, Benjamin, EJ, Franks, PW, Clarke, R, Wilde, AAM, Trip, MD, Steri, M, Witteman, JCM, Qi, L, van der Schoot, CE, de Faire, U, Erdmann, J, Stringham, HM, Koenig, W, Rader, DJ, Melzer, D, Reich, D, Psaty, BM, Kleber, ME, Panagiotakos, DB, Willeit, J, Wennberg, P, Woodward, M, Adamovic, S, Rimm, EB, Meade, TW, Gillum, RF, Shaffer, JA, Hofman, B, Onat, A, Sundstrom, J, Wassertheil-Smoller, S, Mellstrom, D, Gallacher, J, Cushman, M, Tracy, RP, Kauhanen, J, Karlsson, M, Salonen, JT, Wilhelmsen, L, Amouyel, P, Cantin, B, Best, LG, Ben-Shlomo, Y, Manson, JE, Davey-Smith, G, de Bakker, PIW, O'Donnell, CJ, Wilson, JF, Wilson, AG, Assimes, TL, Jansson, JO, Ohlsson, C, Tivesten, A, Ljunggren, O, Reilly, MP, Hamsten, A, Ingelsson, E, Cambien, F, Hung, J, Thomas, GN, Boehnke, M, Schunkert, H, Asselbergs, FW, Kastelein, JJP, Gudnason, V, Salomaa, V, Harris, TB, Kooner, JS, Allin, KH, Nordestgaard, BG, Hopewell, JC, Goodall, AH, Ridker, PM, Holm, H, Watkins, H, Ouwehand, WH, Samani, NJ, Kaptoge, S, Di Angelantonio, E, Harari, O & Danesh, J 2012, 'Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies', Lancet (UK), vol. 379, no. 9822, pp. 1205-1213. https://doi.org/10.1016/S0140-6736(11)61931-4

TY - JOUR

T1 - Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies

AU - Sarwar, N

AU - Butterworth, AS

AU - Freitag, DF

AU - Gregson, J

AU - Willeit, P

AU - Gorman, DN

AU - Gao, P

AU - Saleheen, D

AU - Rendon, A

AU - Nelson, CP

AU - Braund, PS

AU - Hall, AS

AU - Chasman, DI

AU - Tybjaerg-Hansen, A

AU - Chambers, JC

AU - Benjamin, EJ

AU - Franks, PW

AU - Clarke, R

AU - Wilde, AAM

AU - Trip, MD

AU - Steri, M

AU - Witteman, JCM

AU - Qi, L

AU - van der Schoot, CE

AU - de Faire, U

AU - Erdmann, J

AU - Stringham, HM

AU - Koenig, W

AU - Rader, DJ

AU - Melzer, D

AU - Reich, D

AU - Psaty, BM

AU - Kleber, ME

AU - Panagiotakos, DB

AU - Willeit, J

AU - Wennberg, P

AU - Woodward, M

AU - Adamovic, S

AU - Rimm, EB

AU - Meade, TW

AU - Gillum, RF

AU - Shaffer, JA

AU - Hofman, Bert

AU - Onat, A

AU - Sundstrom, J

AU - Wassertheil-Smoller, S

AU - Mellstrom, D

AU - Gallacher, J

AU - Cushman, M

AU - Tracy, RP

AU - Kauhanen, J

AU - Karlsson, M

AU - Salonen, JT

AU - Wilhelmsen, L

AU - Amouyel, P

AU - Cantin, B

AU - Best, LG

AU - Ben-Shlomo, Y

AU - Manson, JE

AU - Davey-Smith, G

AU - de Bakker, PIW

AU - O'Donnell, CJ

AU - Wilson, JF

AU - Wilson, AG

AU - Assimes, TL

AU - Jansson, JO

AU - Ohlsson, C

AU - Tivesten, A

AU - Ljunggren, O

AU - Reilly, MP

AU - Hamsten, A

AU - Ingelsson, E

AU - Cambien, F

AU - Hung, J

AU - Thomas, GN

AU - Boehnke, M

AU - Schunkert, H

AU - Asselbergs, FW

AU - Kastelein, JJP

AU - Gudnason, V

AU - Salomaa, V

AU - Harris, TB

AU - Kooner, JS

AU - Allin, KH

AU - Nordestgaard, BG

AU - Hopewell, JC

AU - Goodall, AH

AU - Ridker, PM

AU - Holm, H

AU - Watkins, H

AU - Ouwehand, WH

AU - Samani, NJ

AU - Kaptoge, S

AU - Di Angelantonio, E

AU - Harari, O

AU - Danesh, J

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 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 Interpretation Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease.

U2 - 10.1016/S0140-6736(11)61931-4

DO - 10.1016/S0140-6736(11)61931-4

M3 - Article

SN - 0140-6736

VL - 379

SP - 1205

EP - 1213

JO - Lancet (UK)

JF - Lancet (UK)

IS - 9822

ER -