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

Freitag, Daniel F.; Butterworth, Adam S.; Willeit, Peter; Howson, Joanna M. M.; Burgess, Stephen; Kaptoge, Stephen; Young, Robin; Ho, Weang Kee; Wood, Angela M. and Sweeting, Michael, et al. (2015) In The Lancet Diabetes & Endocrinology 3(4). p.243-253
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... (More)
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. (Less)
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The Lancet Diabetes & Endocrinology
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3
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4
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243 - 253
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Elsevier
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  • wos:000353032600020
  • scopus:84925298675
ISSN
2213-8595
DOI
10.1016/S2213-8587(15)00034-0
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English
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@article{38d43ebc-23ae-4f77-899b-3d82e399b692,
  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 Willeit, Peter and Howson, Joanna M. M. and Burgess, Stephen and Kaptoge, Stephen and Young, Robin and Ho, Weang Kee and Wood, Angela M. and Sweeting, Michael and Spackman, Sarah and Staley, James R. and Ramond, Anna and Harshfield, Eric and Nielsen, Sune F. and Grande, Peer and Lange, Leslie A. and Bown, Matthew J. and Jones, Gregory T. and Scott, Robert A. and Bevan, Steve and Porcu, Eleonora and Thorleifsson, Gudmar and Zeng, Lingyao and Kessler, Thorsten and Nikpay, Majid and Do, Ron and Zhang, Weihua and Hopewell, Jemma C. and Kleber, Marcus and Delgado, Graciela E. and Nelson, Christopher P. and Goel, Anuj and Bis, Joshua C. and Dehghan, Abbas and Ligthart, Symen and Smith, Albert V. and Qu, Liming and van 't Hof, Femke N. G. and de Bakker, Paul I. W. and Baas, Annette F. and van Rij, Andre and Tromp, Gerard and Kuivaniemi, Helena and Ritchie, Marylyn D. and Verma, Shefali S. and Crawford, Dana C. and Malinowski, Jennifer and de Andrade, Mariza and Kullo, Iftikhar J. and Peissig, Peggy L. and McCarty, Catherine A. and Boettinger, Erwin P. and Gottesman, Omri and Crosslin, David R. and Carrell, David S. and Rasmussen-Torvik, Laura J. and Pacheco, Jennifer A. and Huang, Jie and Timpson, Nicholas J. and Kettunen, Johannes and Ala-Korpela, Mika and Mitchell, Gary F. and Parsa, Afshin and Wilkinson, Ian B. and Gorski, Mathias and Li, Yong and Franceschini, Nora and Keller, Margaux F. and Ganesh, Santhi K. and Langefeld, Carl D. and Bruijn, Lucie and Brown, Matthew A. and Evans, David M. and Baltic, Svetlana and Ferreira, Manuel A. and Baurecht, Hansjoerg and Weidinger, Stephan and Franke, Andre and Lubitz, Steven A. and Mueller-Nurasyid, Martina and Felix, Janine F. and Smith, Nicholas L. and Sudman, Marc and Thompson, Susan D. and Zeggini, Eleftheria and Panoutsopoulou, Kalliope and Nalls, Mike A. and Singleton, Andrew and Polychronakos, Constantin and Bradfield, Jonathan P. and Hakonarson, Hakon and Easton, Douglas F. and Thompson, Deborah and Tomlinson, Ian P. and Dunlop, Malcolm and Hemminki, Kari and Morgan, Gareth and Eisen, Timothy and Goldschmidt, Hartmut and Allan, James M. and Henrion, Marc and Whiffin, Nicola and Wang, Yufei and Chubb, Daniel and Houlston, Richard S. and Iles, Mark M. and Bishop, D. Timothy and Law, Matthew H. and Hayward, Nicholas K. and Luo, Yang and Nejentsev, Sergey and Barbalic, Maja and Crossman, David and Sanna, Serena and Soranzo, Nicole and Markus, Hugh S. and Wareham, Nicholas J. and Rader, Daniel J. and Reilly, Muredach and Assimes, Themistocles and Harris, Tamara B. and Hofman, Albert and Franco, Oscar H. and Gudnason, Vilmundur and Tracy, Russell and Psaty, Bruce M. and Farrall, Martin and Watkins, Hugh and Hall, Alistair S. and Samani, Nilesh J. and Maerz, Winfried and Clarke, Robert and Collins, Rory and Kooner, Jaspal S. and Chambers, John C. and Kathiresan, Sekar and McPherson, Ruth and Erdmann, Jeanette and Kastrati, Adnan and Schunkert, Heribert and Stefansson, Kari and Thorsteinsdottir, Unnur and Walston, Jeremy D. and Tybjaerg-Hansen, Anne and Alam, Dewan S. and Majumder, Abdullah Al Shafi and Di Angelantonio, Emanuele and Chowdhury, Rajiv and Nordestgaard, Borge G. and Saleheen, Danish and Thompson, Simon G. and Danesh, John},
  issn         = {2213-8595},
  language     = {eng},
  number       = {4},
  pages        = {243--253},
  publisher    = {Elsevier},
  series       = {The Lancet Diabetes & Endocrinology},
  title        = {Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis},
  url          = {http://dx.doi.org/10.1016/S2213-8587(15)00034-0},
  volume       = {3},
  year         = {2015},
}