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

Daniel 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 & 133 others 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. Böttinger, 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, Hansjörg Baurecht, Stephan Weidinger, Andre Franke, Steven A. Lubitz, Martina Müller-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, 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 März, Robert Clarke, Rory Collins, Jaspal S. Kooner, John C. Chambers, Sekar Kathiresan, Ruth McPherson, Jeanette Erdmann, Adnan Kastrati, Heribert Schunkert, K. ri Stefánsson, Unnur Thorsteinsdottir, Jeremy D. Walston, Anne Tybjærg-Hansen, Dewan S. Alam, Abdullah Al Shafi Majumder, Emanuele Di Angelantonio, Rajiv Chowdhury, B. rge G. Nordestgaard, Danish Saleheen, Simon G. Thompson, John Danesh, Richard S. Houlston

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

Abstract

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-1α and IL-1β); 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 × 10 -33 ), concentrations of interleukin 6 decreased by 0·02 SD (-0·04 to -0·01; -1·7%; p=3·5 × 10 -3 ), and concentrations of C-reactive protein decreased by 0·03 SD (-0·04 to -0·02; -3·4%; p=7·7 × 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 × 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 × 10 -10 ). Per-allele odds ratios were 0·97 (0·95-0·99; p=9·9 × 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 × 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-1α/β 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. Funding: UK Medical Research Council, British Heart Foundation, UK National Institute for Health Research, National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council, and European Commission Framework Programme 7.
Original languageEnglish
Pages (from-to)243-253
JournalThe Lancet Diabetes and Endocrinology
Volume3
Issue number4
DOIs
Publication statusPublished - 2015
Externally publishedYes

Cite this

Freitag, D., Butterworth, A. S., Willeit, P., Howson, J. M. M., Burgess, S., Kaptoge, S., ... Houlston, R. S. (2015). Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: A Mendelian randomisation analysis. The Lancet Diabetes and Endocrinology, 3(4), 243-253. https://doi.org/10.1016/S2213-8587(15)00034-0
Freitag, Daniel ; Butterworth, Adam S. ; Willeit, Peter ; Howson, Joanna M. M. ; Burgess, Stephen ; Kaptoge, Stephen ; Young, Robin ; Ho, Weang Kee ; Wood, Angela M. ; Sweeting, Michael ; Spackman, Sarah ; Staley, James R. ; Ramond, Anna ; Harshfield, Eric ; Nielsen, Sune F. ; Grande, Peer ; Lange, Leslie A. ; Bown, Matthew J. ; Jones, Gregory T. ; Scott, Robert A. ; Bevan, Steve ; Porcu, Eleonora ; Thorleifsson, Gudmar ; Zeng, Lingyao ; Kessler, Thorsten ; Nikpay, Majid ; Do, Ron ; Zhang, Weihua ; Hopewell, Jemma C. ; Kleber, Marcus ; Delgado, Graciela E. ; Nelson, Christopher P. ; Goel, Anuj ; Bis, Joshua C. ; Dehghan, Abbas ; Ligthart, Symen ; Smith, Albert V. ; Qu, Liming ; van 't Hof, Femke N. G. ; de Bakker, Paul I. W. ; Baas, Annette F. ; van Rij, Andre ; Tromp, Gerard ; Kuivaniemi, Helena ; Ritchie, Marylyn D. ; Verma, Shefali S. ; Crawford, Dana C. ; Malinowski, Jennifer ; de Andrade, Mariza ; Kullo, Iftikhar J. ; Peissig, Peggy L. ; McCarty, Catherine A. ; Böttinger, Erwin P. ; Gottesman, Omri ; Crosslin, David R. ; Carrell, David S. ; Rasmussen-Torvik, Laura J. ; Pacheco, Jennifer A. ; Huang, Jie ; Timpson, Nicholas J. ; Kettunen, Johannes ; Ala-Korpela, Mika ; Mitchell, Gary F. ; Parsa, Afshin ; Wilkinson, Ian B. ; Gorski, Mathias ; Li, Yong ; Franceschini, Nora ; Keller, Margaux F. ; Ganesh, Santhi K. ; Langefeld, Carl D. ; Bruijn, Lucie ; Brown, Matthew A. ; Evans, David M. ; Baltic, Svetlana ; Ferreira, Manuel A. ; Baurecht, Hansjörg ; Weidinger, Stephan ; Franke, Andre ; Lubitz, Steven A. ; Müller-Nurasyid, Martina ; Felix, Janine F. ; Smith, Nicholas L. ; Sudman, Marc ; Thompson, Susan D. ; Zeggini, Eleftheria ; Panoutsopoulou, Kalliope ; Nalls, Mike A. ; Singleton, Andrew ; Polychronakos, Constantin ; Bradfield, Jonathan P. ; Hakonarson, Hakon ; Easton, Douglas F. ; Thompson, Deborah ; Tomlinson, Ian P. ; Dunlop, Malcolm ; Hemminki, Kari ; Morgan, Gareth ; Eisen, Timothy ; Goldschmidt, Hartmut ; Allan, James M. ; Henrion, Marc ; Whiffin, Nicola ; Wang, Yufei ; Chubb, Daniel ; Iles, Mark M. ; Bishop, D. Timothy ; Law, Matthew H. ; Hayward, Nicholas K. ; Luo, Yang ; Nejentsev, Sergey ; Barbalic, Maja ; Crossman, David ; Sanna, Serena ; Soranzo, Nicole ; Markus, Hugh S. ; Wareham, Nicholas J. ; Rader, Daniel J. ; Reilly, Muredach ; Assimes, Themistocles ; Harris, Tamara B. ; Hofman, Albert ; Franco, Oscar H. ; Gudnason, Vilmundur ; Tracy, Russell ; Psaty, Bruce M. ; Farrall, Martin ; Watkins, Hugh ; Hall, Alistair S. ; Samani, Nilesh J. ; März, Winfried ; Clarke, Robert ; Collins, Rory ; Kooner, Jaspal S. ; Chambers, John C. ; Kathiresan, Sekar ; McPherson, Ruth ; Erdmann, Jeanette ; Kastrati, Adnan ; Schunkert, Heribert ; Stefánsson, K. ri ; Thorsteinsdottir, Unnur ; Walston, Jeremy D. ; Tybjærg-Hansen, Anne ; Alam, Dewan S. ; Al Shafi Majumder, Abdullah ; Angelantonio, Emanuele Di ; Chowdhury, Rajiv ; Nordestgaard, B. rge G. ; Saleheen, Danish ; Thompson, Simon G. ; Danesh, John ; Houlston, Richard S. / Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: A Mendelian randomisation analysis. In: The Lancet Diabetes and Endocrinology. 2015 ; Vol. 3, No. 4. pp. 243-253.
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title = "Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: A Mendelian randomisation analysis",
abstract = "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-1α and IL-1β); 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 × 10 -33 ), concentrations of interleukin 6 decreased by 0·02 SD (-0·04 to -0·01; -1·7{\%}; p=3·5 × 10 -3 ), and concentrations of C-reactive protein decreased by 0·03 SD (-0·04 to -0·02; -3·4{\%}; p=7·7 × 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 × 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 × 10 -10 ). Per-allele odds ratios were 0·97 (0·95-0·99; p=9·9 × 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 × 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-1α/β 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. Funding: UK Medical Research Council, British Heart Foundation, UK National Institute for Health Research, National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council, and European Commission Framework Programme 7.",
author = "Daniel Freitag 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 B{\"o}ttinger, {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 Hansj{\"o}rg Baurecht and Stephan Weidinger and Andre Franke and Lubitz, {Steven A.} and Martina M{\"u}ller-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 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 M{\"a}rz 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 Stef{\'a}nsson, {K. ri} and Unnur Thorsteinsdottir and Walston, {Jeremy D.} and Anne Tybj{\ae}rg-Hansen and Alam, {Dewan S.} and {Al Shafi Majumder}, Abdullah and Angelantonio, {Emanuele Di} and Rajiv Chowdhury and Nordestgaard, {B. rge G.} and Danish Saleheen and Thompson, {Simon G.} and John Danesh and Houlston, {Richard S.}",
year = "2015",
doi = "10.1016/S2213-8587(15)00034-0",
language = "English",
volume = "3",
pages = "243--253",
journal = "Lancet diabetes & endocrinology",
issn = "2213-8587",
publisher = "Elsevier BV",
number = "4",

}

Freitag, D, 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, Böttinger, 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, Müller-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, 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, März, W, Clarke, R, Collins, R, Kooner, JS, Chambers, JC, Kathiresan, S, McPherson, R, Erdmann, J, Kastrati, A, Schunkert, H, Stefánsson, KR, Thorsteinsdottir, U, Walston, JD, Tybjærg-Hansen, A, Alam, DS, Al Shafi Majumder, A, Angelantonio, ED, Chowdhury, R, Nordestgaard, BRG, Saleheen, D, Thompson, SG, Danesh, J & Houlston, RS 2015, 'Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: A Mendelian randomisation analysis' The Lancet Diabetes and Endocrinology, vol. 3, no. 4, pp. 243-253. https://doi.org/10.1016/S2213-8587(15)00034-0

Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: A Mendelian randomisation analysis. / Freitag, Daniel; Butterworth, Adam S.; Willeit, Peter; Howson, Joanna M. M.; Burgess, Stephen; Kaptoge, Stephen; Young, Robin; Ho, Weang Kee; Wood, Angela M.; Sweeting, Michael; Spackman, Sarah; Staley, James R.; Ramond, Anna; Harshfield, Eric; Nielsen, Sune F.; Grande, Peer; Lange, Leslie A.; Bown, Matthew J.; Jones, Gregory T.; Scott, Robert A.; Bevan, Steve; Porcu, Eleonora; Thorleifsson, Gudmar; Zeng, Lingyao; Kessler, Thorsten; Nikpay, Majid; Do, Ron; Zhang, Weihua; Hopewell, Jemma C.; Kleber, Marcus; Delgado, Graciela E.; Nelson, Christopher P.; Goel, Anuj; Bis, Joshua C.; Dehghan, Abbas; Ligthart, Symen; Smith, Albert V.; Qu, Liming; van 't Hof, Femke N. G.; de Bakker, Paul I. W.; Baas, Annette F.; van Rij, Andre; Tromp, Gerard; Kuivaniemi, Helena; Ritchie, Marylyn D.; Verma, Shefali S.; Crawford, Dana C.; Malinowski, Jennifer; de Andrade, Mariza; Kullo, Iftikhar J.; Peissig, Peggy L.; McCarty, Catherine A.; Böttinger, Erwin P.; Gottesman, Omri; Crosslin, David R.; Carrell, David S.; Rasmussen-Torvik, Laura J.; Pacheco, Jennifer A.; Huang, Jie; Timpson, Nicholas J.; Kettunen, Johannes; Ala-Korpela, Mika; Mitchell, Gary F.; Parsa, Afshin; Wilkinson, Ian B.; Gorski, Mathias; Li, Yong; Franceschini, Nora; Keller, Margaux F.; Ganesh, Santhi K.; Langefeld, Carl D.; Bruijn, Lucie; Brown, Matthew A.; Evans, David M.; Baltic, Svetlana; Ferreira, Manuel A.; Baurecht, Hansjörg; Weidinger, Stephan; Franke, Andre; Lubitz, Steven A.; Müller-Nurasyid, Martina; Felix, Janine F.; Smith, Nicholas L.; Sudman, Marc; Thompson, Susan D.; Zeggini, Eleftheria; Panoutsopoulou, Kalliope; Nalls, Mike A.; Singleton, Andrew; Polychronakos, Constantin; Bradfield, Jonathan P.; Hakonarson, Hakon; Easton, Douglas F.; Thompson, Deborah; Tomlinson, Ian P.; Dunlop, Malcolm; Hemminki, Kari; Morgan, Gareth; Eisen, Timothy; Goldschmidt, Hartmut; Allan, James M.; Henrion, Marc; Whiffin, Nicola; Wang, Yufei; Chubb, Daniel; Iles, Mark M.; Bishop, D. Timothy; Law, Matthew H.; Hayward, Nicholas K.; Luo, Yang; Nejentsev, Sergey; Barbalic, Maja; Crossman, David; Sanna, Serena; Soranzo, Nicole; Markus, Hugh S.; Wareham, Nicholas J.; Rader, Daniel J.; Reilly, Muredach; Assimes, Themistocles; Harris, Tamara B.; Hofman, Albert; Franco, Oscar H.; Gudnason, Vilmundur; Tracy, Russell; Psaty, Bruce M.; Farrall, Martin; Watkins, Hugh; Hall, Alistair S.; Samani, Nilesh J.; März, Winfried; Clarke, Robert; Collins, Rory; Kooner, Jaspal S.; Chambers, John C.; Kathiresan, Sekar; McPherson, Ruth; Erdmann, Jeanette; Kastrati, Adnan; Schunkert, Heribert; Stefánsson, K. ri; Thorsteinsdottir, Unnur; Walston, Jeremy D.; Tybjærg-Hansen, Anne; Alam, Dewan S.; Al Shafi Majumder, Abdullah; Angelantonio, Emanuele Di; Chowdhury, Rajiv; Nordestgaard, B. rge G.; Saleheen, Danish; Thompson, Simon G.; Danesh, John; Houlston, Richard S.

In: The Lancet Diabetes and Endocrinology, Vol. 3, No. 4, 2015, p. 243-253.

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

TY - JOUR

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

AU - Freitag, Daniel

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 - Böttinger, 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, Hansjörg

AU - Weidinger, Stephan

AU - Franke, Andre

AU - Lubitz, Steven A.

AU - Müller-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 - 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 - März, 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 - Stefánsson, K. ri

AU - Thorsteinsdottir, Unnur

AU - Walston, Jeremy D.

AU - Tybjærg-Hansen, Anne

AU - Alam, Dewan S.

AU - Al Shafi Majumder, Abdullah

AU - Angelantonio, Emanuele Di

AU - Chowdhury, Rajiv

AU - Nordestgaard, B. rge G.

AU - Saleheen, Danish

AU - Thompson, Simon G.

AU - Danesh, John

AU - Houlston, Richard S.

PY - 2015

Y1 - 2015

N2 - 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-1α and IL-1β); 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 × 10 -33 ), concentrations of interleukin 6 decreased by 0·02 SD (-0·04 to -0·01; -1·7%; p=3·5 × 10 -3 ), and concentrations of C-reactive protein decreased by 0·03 SD (-0·04 to -0·02; -3·4%; p=7·7 × 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 × 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 × 10 -10 ). Per-allele odds ratios were 0·97 (0·95-0·99; p=9·9 × 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 × 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-1α/β 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. Funding: UK Medical Research Council, British Heart Foundation, UK National Institute for Health Research, National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council, and European Commission Framework Programme 7.

AB - 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-1α and IL-1β); 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 × 10 -33 ), concentrations of interleukin 6 decreased by 0·02 SD (-0·04 to -0·01; -1·7%; p=3·5 × 10 -3 ), and concentrations of C-reactive protein decreased by 0·03 SD (-0·04 to -0·02; -3·4%; p=7·7 × 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 × 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 × 10 -10 ). Per-allele odds ratios were 0·97 (0·95-0·99; p=9·9 × 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 × 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-1α/β 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. Funding: UK Medical Research Council, British Heart Foundation, UK National Institute for Health Research, National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council, and European Commission Framework Programme 7.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84925298675&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/25726324

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

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

M3 - Article

VL - 3

SP - 243

EP - 253

JO - Lancet diabetes & endocrinology

JF - Lancet diabetes & endocrinology

SN - 2213-8587

IS - 4

ER -

Freitag D, Butterworth AS, Willeit P, Howson JMM, Burgess S, Kaptoge S et al. Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: A Mendelian randomisation analysis. The Lancet Diabetes and Endocrinology. 2015;3(4):243-253. https://doi.org/10.1016/S2213-8587(15)00034-0

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