Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis

Daniel F. Freitag; Adam S. Butterworth; Peter Willeit; Joanna M. M. Howson; Stephen Burgess; Stephen Kaptoge; Robin Young; Weang Kee Ho; Angela M. Wood; Michael Sweeting; Sarah Spackman; James R. Staley; Anna Ramond; Eric Harshfield; Sune F. Nielsen; Peer Grande; Leslie A. Lange; Matthew J. Bown; Gregory T. Jones; Robert A. Scott; Steve Bevan; Eleonora Porcu; Gudmar Thorleifsson; Lingyao Zeng; Thorsten Kessler; Majid Nikpay; Ron Do; Weihua Zhang; Jemma C. Hopewell; Marcus Kleber; Graciela E. Delgado; Christopher P. Nelson; Anuj Goel; Joshua C. Bis; Abbas Dehghan; Symen Ligthart; Albert V. Smith; Liming Qu; Femke N. G. van 't Hof; Paul I. W. de Bakker; Annette F. Baas; Andre van Rij; Gerard Tromp; Helena Kuivaniemi; Marylyn D. Ritchie; Shefali S. Verma; Dana C. Crawford; Jennifer Malinowski; Mariza de Andrade; Iftikhar J. Kullo; Peggy L. Peissig; Catherine A. McCarty; Erwin P. Boettinger; Omri Gottesman; David R. Crosslin; David S. Carrell; Laura J. Rasmussen-Torvik; Jennifer A. Pacheco; Jie Huang; Nicholas J. Timpson; Johannes Kettunen; Mika Ala-Korpela; Gary F. Mitchell; Afshin Parsa; Ian B. Wilkinson; Mathias Gorski; Yong Li; Nora Franceschini; Margaux F. Keller; Santhi K. Ganesh; Carl D. Langefeld; Lucie Bruijn; Matthew A. Brown; David M. Evans; Svetlana Baltic; Manuel A. Ferreira; Hansjoerg Baurecht; Stephan Weidinger; Andre Franke; Steven A. Lubitz; Martina Mueller-Nurasyid; Janine F. Felix; Nicholas L. Smith; Marc Sudman; Susan D. Thompson; Eleftheria Zeggini; Kalliope Panoutsopoulou; Mike A. Nalls; Andrew Singleton; Constantin Polychronakos; Jonathan P. Bradfield; Hakon Hakonarson; Douglas F. Easton; Deborah Thompson; Ian P. Tomlinson; Malcolm Dunlop; Kari Hemminki; Gareth Morgan; Timothy Eisen; Hartmut Goldschmidt; James M. Allan; Marc Henrion; Nicola Whiffin; Yufei Wang; Daniel Chubb; Richard S. Houlston; Mark M. Iles; D. Timothy Bishop; Matthew H. Law; Nicholas K. Hayward; Yang Luo; Sergey Nejentsev; Maja Barbalic; David Crossman; Serena Sanna; Nicole Soranzo; Hugh S. Markus; Nicholas J. Wareham; Daniel J. Rader; Muredach Reilly; Themistocles Assimes; Tamara B. Harris; Albert Hofman; Oscar H. Franco; Vilmundur Gudnason; Russell Tracy; Bruce M. Psaty; Martin Farrall; Hugh Watkins; Alistair S. Hall; Nilesh J. Samani; Winfried Maerz; Robert Clarke; Rory Collins; Jaspal S. Kooner; John C. Chambers; Sekar Kathiresan; Ruth McPherson; Jeanette Erdmann; Adnan Kastrati; Heribert Schunkert; Kari Stefansson; Unnur Thorsteinsdottir; Jeremy D. Walston; Anne Tybjaerg-Hansen; Dewan S. Alam; Abdullah Al Shafi Majumder; Emanuele Di Angelantonio; Rajiv Chowdhury; Borge G. Nordestgaard; Danish Saleheen; Simon G. Thompson; John Danesh

doi:10.1016/S2213-8587(15)00034-0

Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis

Daniel F. Freitag, Adam S. Butterworth, Peter Willeit, Joanna M. M. Howson, Stephen Burgess, Stephen Kaptoge, Robin Young, Weang Kee Ho, Angela M. Wood, Michael Sweeting, Sarah Spackman, James R. Staley, Anna Ramond, Eric Harshfield, Sune F. Nielsen, Peer Grande, Leslie A. Lange, Matthew J. Bown, Gregory T. Jones, Robert A. ScottSteve Bevan, Eleonora Porcu, Gudmar Thorleifsson, Lingyao Zeng, Thorsten Kessler, Majid Nikpay, Ron Do, Weihua Zhang, Jemma C. Hopewell, Marcus Kleber, Graciela E. Delgado, Christopher P. Nelson, Anuj Goel, Joshua C. Bis, Abbas Dehghan, Symen Ligthart, Albert V. Smith, Liming Qu, Femke N. G. van 't Hof, Paul I. W. de Bakker, Annette F. Baas, Andre van Rij, Gerard Tromp, Helena Kuivaniemi, Marylyn D. Ritchie, Shefali S. Verma, Dana C. Crawford, Jennifer Malinowski, Mariza de Andrade, Iftikhar J. Kullo, Peggy L. Peissig, Catherine A. McCarty, Erwin P. Boettinger, Omri Gottesman, David R. Crosslin, David S. Carrell, Laura J. Rasmussen-Torvik, Jennifer A. Pacheco, Jie Huang, Nicholas J. Timpson, Johannes Kettunen, Mika Ala-Korpela, Gary F. Mitchell, Afshin Parsa, Ian B. Wilkinson, Mathias Gorski, Yong Li, Nora Franceschini, Margaux F. Keller, Santhi K. Ganesh, Carl D. Langefeld, Lucie Bruijn, Matthew A. Brown, David M. Evans, Svetlana Baltic, Manuel A. Ferreira, Hansjoerg Baurecht, Stephan Weidinger, Andre Franke, Steven A. Lubitz, Martina Mueller-Nurasyid, Janine F. Felix, Nicholas L. Smith, Marc Sudman, Susan D. Thompson, Eleftheria Zeggini, Kalliope Panoutsopoulou, Mike A. Nalls, Andrew Singleton, Constantin Polychronakos, Jonathan P. Bradfield, Hakon Hakonarson, Douglas F. Easton, Deborah Thompson, Ian P. Tomlinson, Malcolm Dunlop, Kari Hemminki, Gareth Morgan, Timothy Eisen, Hartmut Goldschmidt, James M. Allan, Marc Henrion, Nicola Whiffin, Yufei Wang, Daniel Chubb, Richard S. Houlston, Mark M. Iles, D. Timothy Bishop, Matthew H. Law, Nicholas K. Hayward, Yang Luo, Sergey Nejentsev, Maja Barbalic, David Crossman, Serena Sanna, Nicole Soranzo, Hugh S. Markus, Nicholas J. Wareham, Daniel J. Rader, Muredach Reilly, Themistocles Assimes, Tamara B. Harris, Albert Hofman, Oscar H. Franco, Vilmundur Gudnason, Russell Tracy, Bruce M. Psaty, Martin Farrall, Hugh Watkins, Alistair S. Hall, Nilesh J. Samani, Winfried Maerz, Robert Clarke, Rory Collins, Jaspal S. Kooner, John C. Chambers, Sekar Kathiresan, Ruth McPherson, Jeanette Erdmann, Adnan Kastrati, Heribert Schunkert, Kari Stefansson, Unnur Thorsteinsdottir, Jeremy D. Walston, Anne Tybjaerg-Hansen, Dewan S. Alam, Abdullah Al Shafi Majumder, Emanuele Di Angelantonio, Rajiv Chowdhury, Borge G. Nordestgaard, Danish Saleheen, Simon G. Thompson, John Danesh

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Abstract

Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1 alpha and IL-1 beta); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p=9.3 x 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1,7%; p=3.5 x 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p=7.7 x 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p=1.8 x 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p=3.9 x 10(-10)). Perallele odds ratios were 0.97 (0.95-0.99; p=9.9 x 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p=0.47) for type 2 diabetes, 1.00 (0.98-1.02; p=0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p=1.8 x 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Interpretation Human genetic data suggest that long-term dual IL-1 alpha/beta inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. Copyright (C) The Interleukin 1 Genetics Consortium. Open Access article distributed under the terms of CC-BY-NC-ND.

Original language	English
Pages (from-to)	243-253
Journal	The Lancet Diabetes & Endocrinology
Volume	3
Issue number	4
DOIs	https://doi.org/10.1016/S2213-8587(15)00034-0
Publication status	Published - 2015

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Endocrinology and Diabetes

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/S2213-8587(15)00034-0

Lancet_Diabetes_Endocrinol_Freitag_et_al

Cite this

Freitag, D. F., Butterworth, A. S., Willeit, P., Howson, J. M. M., Burgess, S., Kaptoge, S., Young, R., Ho, W. K., Wood, A. M., Sweeting, M., Spackman, S., Staley, J. R., Ramond, A., Harshfield, E., Nielsen, S. F., Grande, P., Lange, L. A., Bown, M. J., Jones, G. T., ... Danesh, J. (2015). Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis. The Lancet Diabetes & Endocrinology, 3(4), 243-253. https://doi.org/10.1016/S2213-8587(15)00034-0

@article{38d43ebc23ae4f77899b3d82e399b692,

title = "Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis",

abstract = "Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1 alpha and IL-1 beta); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p=9.3 x 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1,7%; p=3.5 x 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p=7.7 x 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p=1.8 x 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p=3.9 x 10(-10)). Perallele odds ratios were 0.97 (0.95-0.99; p=9.9 x 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p=0.47) for type 2 diabetes, 1.00 (0.98-1.02; p=0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p=1.8 x 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Interpretation Human genetic data suggest that long-term dual IL-1 alpha/beta inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. Copyright (C) The Interleukin 1 Genetics Consortium. Open Access article distributed under the terms of CC-BY-NC-ND.",

author = "Freitag, {Daniel F.} and Butterworth, {Adam S.} and Peter Willeit and Howson, {Joanna M. M.} and Stephen Burgess and Stephen Kaptoge and Robin Young and Ho, {Weang Kee} and Wood, {Angela M.} and Michael Sweeting and Sarah Spackman and Staley, {James R.} and Anna Ramond and Eric Harshfield and Nielsen, {Sune F.} and Peer Grande and Lange, {Leslie A.} and Bown, {Matthew J.} and Jones, {Gregory T.} and Scott, {Robert A.} and Steve Bevan and Eleonora Porcu and Gudmar Thorleifsson and Lingyao Zeng and Thorsten Kessler and Majid Nikpay and Ron Do and Weihua Zhang and Hopewell, {Jemma C.} and Marcus Kleber and Delgado, {Graciela E.} and Nelson, {Christopher P.} and Anuj Goel and Bis, {Joshua C.} and Abbas Dehghan and Symen Ligthart and Smith, {Albert V.} and Liming Qu and {van 't Hof}, {Femke N. G.} and {de Bakker}, {Paul I. W.} and Baas, {Annette F.} and {van Rij}, Andre and Gerard Tromp and Helena Kuivaniemi and Ritchie, {Marylyn D.} and Verma, {Shefali S.} and Crawford, {Dana C.} and Jennifer Malinowski and {de Andrade}, Mariza and Kullo, {Iftikhar J.} and Peissig, {Peggy L.} and McCarty, {Catherine A.} and Boettinger, {Erwin P.} and Omri Gottesman and Crosslin, {David R.} and Carrell, {David S.} and Rasmussen-Torvik, {Laura J.} and Pacheco, {Jennifer A.} and Jie Huang and Timpson, {Nicholas J.} and Johannes Kettunen and Mika Ala-Korpela and Mitchell, {Gary F.} and Afshin Parsa and Wilkinson, {Ian B.} and Mathias Gorski and Yong Li and Nora Franceschini and Keller, {Margaux F.} and Ganesh, {Santhi K.} and Langefeld, {Carl D.} and Lucie Bruijn and Brown, {Matthew A.} and Evans, {David M.} and Svetlana Baltic and Ferreira, {Manuel A.} and Hansjoerg Baurecht and Stephan Weidinger and Andre Franke and Lubitz, {Steven A.} and Martina Mueller-Nurasyid and Felix, {Janine F.} and Smith, {Nicholas L.} and Marc Sudman and Thompson, {Susan D.} and Eleftheria Zeggini and Kalliope Panoutsopoulou and Nalls, {Mike A.} and Andrew Singleton and Constantin Polychronakos and Bradfield, {Jonathan P.} and Hakon Hakonarson and Easton, {Douglas F.} and Deborah Thompson and Tomlinson, {Ian P.} and Malcolm Dunlop and Kari Hemminki and Gareth Morgan and Timothy Eisen and Hartmut Goldschmidt and Allan, {James M.} and Marc Henrion and Nicola Whiffin and Yufei Wang and Daniel Chubb and Houlston, {Richard S.} and Iles, {Mark M.} and Bishop, {D. Timothy} and Law, {Matthew H.} and Hayward, {Nicholas K.} and Yang Luo and Sergey Nejentsev and Maja Barbalic and David Crossman and Serena Sanna and Nicole Soranzo and Markus, {Hugh S.} and Wareham, {Nicholas J.} and Rader, {Daniel J.} and Muredach Reilly and Themistocles Assimes and Harris, {Tamara B.} and Albert Hofman and Franco, {Oscar H.} and Vilmundur Gudnason and Russell Tracy and Psaty, {Bruce M.} and Martin Farrall and Hugh Watkins and Hall, {Alistair S.} and Samani, {Nilesh J.} and Winfried Maerz and Robert Clarke and Rory Collins and Kooner, {Jaspal S.} and Chambers, {John C.} and Sekar Kathiresan and Ruth McPherson and Jeanette Erdmann and Adnan Kastrati and Heribert Schunkert and Kari Stefansson and Unnur Thorsteinsdottir and Walston, {Jeremy D.} and Anne Tybjaerg-Hansen and Alam, {Dewan S.} and Majumder, {Abdullah Al Shafi} and {Di Angelantonio}, Emanuele and Rajiv Chowdhury and Nordestgaard, {Borge G.} and Danish Saleheen and Thompson, {Simon G.} and John Danesh",

year = "2015",

doi = "10.1016/S2213-8587(15)00034-0",

language = "English",

volume = "3",

pages = "243--253",

journal = "The Lancet Diabetes & Endocrinology",

issn = "2213-8595",

publisher = "Elsevier",

number = "4",

}

Freitag, DF, Butterworth, AS, Willeit, P, Howson, JMM, Burgess, S, Kaptoge, S, Young, R, Ho, WK, Wood, AM, Sweeting, M, Spackman, S, Staley, JR, Ramond, A, Harshfield, E, Nielsen, SF, Grande, P, Lange, LA, Bown, MJ, Jones, GT, Scott, RA, Bevan, S, Porcu, E, Thorleifsson, G, Zeng, L, Kessler, T, Nikpay, M, Do, R, Zhang, W, Hopewell, JC, Kleber, M, Delgado, GE, Nelson, CP, Goel, A, Bis, JC, Dehghan, A, Ligthart, S, Smith, AV, Qu, L, van 't Hof, FNG, de Bakker, PIW, Baas, AF, van Rij, A, Tromp, G, Kuivaniemi, H, Ritchie, MD, Verma, SS, Crawford, DC, Malinowski, J, de Andrade, M, Kullo, IJ, Peissig, PL, McCarty, CA, Boettinger, EP, Gottesman, O, Crosslin, DR, Carrell, DS, Rasmussen-Torvik, LJ, Pacheco, JA, Huang, J, Timpson, NJ, Kettunen, J, Ala-Korpela, M, Mitchell, GF, Parsa, A, Wilkinson, IB, Gorski, M, Li, Y, Franceschini, N, Keller, MF, Ganesh, SK, Langefeld, CD, Bruijn, L, Brown, MA, Evans, DM, Baltic, S, Ferreira, MA, Baurecht, H, Weidinger, S, Franke, A, Lubitz, SA, Mueller-Nurasyid, M, Felix, JF, Smith, NL, Sudman, M, Thompson, SD, Zeggini, E, Panoutsopoulou, K, Nalls, MA, Singleton, A, Polychronakos, C, Bradfield, JP, Hakonarson, H, Easton, DF, Thompson, D, Tomlinson, IP, Dunlop, M, Hemminki, K, Morgan, G, Eisen, T, Goldschmidt, H, Allan, JM, Henrion, M, Whiffin, N, Wang, Y, Chubb, D, Houlston, RS, Iles, MM, Bishop, DT, Law, MH, Hayward, NK, Luo, Y, Nejentsev, S, Barbalic, M, Crossman, D, Sanna, S, Soranzo, N, Markus, HS, Wareham, NJ, Rader, DJ, Reilly, M, Assimes, T, Harris, TB, Hofman, A, Franco, OH, Gudnason, V, Tracy, R, Psaty, BM, Farrall, M, Watkins, H, Hall, AS, Samani, NJ, Maerz, W, Clarke, R, Collins, R, Kooner, JS, Chambers, JC, Kathiresan, S, McPherson, R, Erdmann, J, Kastrati, A, Schunkert, H, Stefansson, K, Thorsteinsdottir, U, Walston, JD, Tybjaerg-Hansen, A, Alam, DS, Majumder, AAS, Di Angelantonio, E, Chowdhury, R, Nordestgaard, BG, Saleheen, D, Thompson, SG & Danesh, J 2015, 'Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis', The Lancet Diabetes & Endocrinology, vol. 3, no. 4, pp. 243-253. https://doi.org/10.1016/S2213-8587(15)00034-0

TY - JOUR

T1 - Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis

AU - Freitag, Daniel F.

AU - Butterworth, Adam S.

AU - Willeit, Peter

AU - Howson, Joanna M. M.

AU - Burgess, Stephen

AU - Kaptoge, Stephen

AU - Young, Robin

AU - Ho, Weang Kee

AU - Wood, Angela M.

AU - Sweeting, Michael

AU - Spackman, Sarah

AU - Staley, James R.

AU - Ramond, Anna

AU - Harshfield, Eric

AU - Nielsen, Sune F.

AU - Grande, Peer

AU - Lange, Leslie A.

AU - Bown, Matthew J.

AU - Jones, Gregory T.

AU - Scott, Robert A.

AU - Bevan, Steve

AU - Porcu, Eleonora

AU - Thorleifsson, Gudmar

AU - Zeng, Lingyao

AU - Kessler, Thorsten

AU - Nikpay, Majid

AU - Do, Ron

AU - Zhang, Weihua

AU - Hopewell, Jemma C.

AU - Kleber, Marcus

AU - Delgado, Graciela E.

AU - Nelson, Christopher P.

AU - Goel, Anuj

AU - Bis, Joshua C.

AU - Dehghan, Abbas

AU - Ligthart, Symen

AU - Smith, Albert V.

AU - Qu, Liming

AU - van 't Hof, Femke N. G.

AU - de Bakker, Paul I. W.

AU - Baas, Annette F.

AU - van Rij, Andre

AU - Tromp, Gerard

AU - Kuivaniemi, Helena

AU - Ritchie, Marylyn D.

AU - Verma, Shefali S.

AU - Crawford, Dana C.

AU - Malinowski, Jennifer

AU - de Andrade, Mariza

AU - Kullo, Iftikhar J.

AU - Peissig, Peggy L.

AU - McCarty, Catherine A.

AU - Boettinger, Erwin P.

AU - Gottesman, Omri

AU - Crosslin, David R.

AU - Carrell, David S.

AU - Rasmussen-Torvik, Laura J.

AU - Pacheco, Jennifer A.

AU - Huang, Jie

AU - Timpson, Nicholas J.

AU - Kettunen, Johannes

AU - Ala-Korpela, Mika

AU - Mitchell, Gary F.

AU - Parsa, Afshin

AU - Wilkinson, Ian B.

AU - Gorski, Mathias

AU - Li, Yong

AU - Franceschini, Nora

AU - Keller, Margaux F.

AU - Ganesh, Santhi K.

AU - Langefeld, Carl D.

AU - Bruijn, Lucie

AU - Brown, Matthew A.

AU - Evans, David M.

AU - Baltic, Svetlana

AU - Ferreira, Manuel A.

AU - Baurecht, Hansjoerg

AU - Weidinger, Stephan

AU - Franke, Andre

AU - Lubitz, Steven A.

AU - Mueller-Nurasyid, Martina

AU - Felix, Janine F.

AU - Smith, Nicholas L.

AU - Sudman, Marc

AU - Thompson, Susan D.

AU - Zeggini, Eleftheria

AU - Panoutsopoulou, Kalliope

AU - Nalls, Mike A.

AU - Singleton, Andrew

AU - Polychronakos, Constantin

AU - Bradfield, Jonathan P.

AU - Hakonarson, Hakon

AU - Easton, Douglas F.

AU - Thompson, Deborah

AU - Tomlinson, Ian P.

AU - Dunlop, Malcolm

AU - Hemminki, Kari

AU - Morgan, Gareth

AU - Eisen, Timothy

AU - Goldschmidt, Hartmut

AU - Allan, James M.

AU - Henrion, Marc

AU - Whiffin, Nicola

AU - Wang, Yufei

AU - Chubb, Daniel

AU - Houlston, Richard S.

AU - Iles, Mark M.

AU - Bishop, D. Timothy

AU - Law, Matthew H.

AU - Hayward, Nicholas K.

AU - Luo, Yang

AU - Nejentsev, Sergey

AU - Barbalic, Maja

AU - Crossman, David

AU - Sanna, Serena

AU - Soranzo, Nicole

AU - Markus, Hugh S.

AU - Wareham, Nicholas J.

AU - Rader, Daniel J.

AU - Reilly, Muredach

AU - Assimes, Themistocles

AU - Harris, Tamara B.

AU - Hofman, Albert

AU - Franco, Oscar H.

AU - Gudnason, Vilmundur

AU - Tracy, Russell

AU - Psaty, Bruce M.

AU - Farrall, Martin

AU - Watkins, Hugh

AU - Hall, Alistair S.

AU - Samani, Nilesh J.

AU - Maerz, Winfried

AU - Clarke, Robert

AU - Collins, Rory

AU - Kooner, Jaspal S.

AU - Chambers, John C.

AU - Kathiresan, Sekar

AU - McPherson, Ruth

AU - Erdmann, Jeanette

AU - Kastrati, Adnan

AU - Schunkert, Heribert

AU - Stefansson, Kari

AU - Thorsteinsdottir, Unnur

AU - Walston, Jeremy D.

AU - Tybjaerg-Hansen, Anne

AU - Alam, Dewan S.

AU - Majumder, Abdullah Al Shafi

AU - Di Angelantonio, Emanuele

AU - Chowdhury, Rajiv

AU - Nordestgaard, Borge G.

AU - Saleheen, Danish

AU - Thompson, Simon G.

AU - Danesh, John

PY - 2015

Y1 - 2015

N2 - Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1 alpha and IL-1 beta); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p=9.3 x 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1,7%; p=3.5 x 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p=7.7 x 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p=1.8 x 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p=3.9 x 10(-10)). Perallele odds ratios were 0.97 (0.95-0.99; p=9.9 x 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p=0.47) for type 2 diabetes, 1.00 (0.98-1.02; p=0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p=1.8 x 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Interpretation Human genetic data suggest that long-term dual IL-1 alpha/beta inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. Copyright (C) The Interleukin 1 Genetics Consortium. Open Access article distributed under the terms of CC-BY-NC-ND.

AB - Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1 alpha and IL-1 beta); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p=9.3 x 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1,7%; p=3.5 x 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p=7.7 x 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p=1.8 x 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p=3.9 x 10(-10)). Perallele odds ratios were 0.97 (0.95-0.99; p=9.9 x 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p=0.47) for type 2 diabetes, 1.00 (0.98-1.02; p=0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p=1.8 x 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Interpretation Human genetic data suggest that long-term dual IL-1 alpha/beta inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. Copyright (C) The Interleukin 1 Genetics Consortium. Open Access article distributed under the terms of CC-BY-NC-ND.

U2 - 10.1016/S2213-8587(15)00034-0

DO - 10.1016/S2213-8587(15)00034-0

M3 - Article

SN - 2213-8595

VL - 3

SP - 243

EP - 253

JO - The Lancet Diabetes & Endocrinology

JF - The Lancet Diabetes & Endocrinology

IS - 4

ER -

Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis

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