Search: onr:"swepub:oai:lup.lub.lu.se:38d43ebc-23ae-4f77-899b-3d82e399b692" > Cardiometabolic eff...
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000 | 10698naa a2202125 4500 | |
001 | oai:lup.lub.lu.se:38d43ebc-23ae-4f77-899b-3d82e399b692 | |
003 | SwePub | |
008 | 160401s2015 | |||||||||||000 ||eng| | |
024 | 7 | a https://lup.lub.lu.se/record/54014272 URI |
024 | 7 | a https://doi.org/10.1016/S2213-8587(15)00034-02 DOI |
040 | a (SwePub)lu | |
041 | a engb eng | |
042 | 9 SwePub | |
072 | 7 | a art2 swepub-publicationtype |
072 | 7 | a ref2 swepub-contenttype |
100 | 1 | a Freitag, Daniel F.4 aut |
245 | 1 0 | a Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis |
264 | 1 | c 2015 |
338 | a electronic2 rdacarrier | |
520 | a 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. | |
650 | 7 | a MEDICIN OCH HÄLSOVETENSKAPx Klinisk medicinx Endokrinologi och diabetes0 (SwePub)302052 hsv//swe |
650 | 7 | a MEDICAL AND HEALTH SCIENCESx Clinical Medicinex Endocrinology and Diabetes0 (SwePub)302052 hsv//eng |
700 | 1 | a Butterworth, Adam S.4 aut |
700 | 1 | a Willeit, Peter4 aut |
700 | 1 | a Howson, Joanna M. M.4 aut |
700 | 1 | a Burgess, Stephen4 aut |
700 | 1 | a Kaptoge, Stephen4 aut |
700 | 1 | a Young, Robin4 aut |
700 | 1 | a Ho, Weang Kee4 aut |
700 | 1 | a Wood, Angela M.4 aut |
700 | 1 | a Sweeting, Michael4 aut |
700 | 1 | a Spackman, Sarah4 aut |
700 | 1 | a Staley, James R.4 aut |
700 | 1 | a Ramond, Anna4 aut |
700 | 1 | a Harshfield, Eric4 aut |
700 | 1 | a Nielsen, Sune F.4 aut |
700 | 1 | a Grande, Peer4 aut |
700 | 1 | a Lange, Leslie A.4 aut |
700 | 1 | a Bown, Matthew J.4 aut |
700 | 1 | a Jones, Gregory T.4 aut |
700 | 1 | a Scott, Robert A.4 aut |
700 | 1 | a Bevan, Steve4 aut |
700 | 1 | a Porcu, Eleonora4 aut |
700 | 1 | a Thorleifsson, Gudmar4 aut |
700 | 1 | a Zeng, Lingyao4 aut |
700 | 1 | a Kessler, Thorsten4 aut |
700 | 1 | a Nikpay, Majid4 aut |
700 | 1 | a Do, Ron4 aut |
700 | 1 | a Zhang, Weihua4 aut |
700 | 1 | a Hopewell, Jemma C.4 aut |
700 | 1 | a Kleber, Marcus4 aut |
700 | 1 | a Delgado, Graciela E.4 aut |
700 | 1 | a Nelson, Christopher P.4 aut |
700 | 1 | a Goel, Anuj4 aut |
700 | 1 | a Bis, Joshua C.4 aut |
700 | 1 | a Dehghan, Abbas4 aut |
700 | 1 | a Ligthart, Symen4 aut |
700 | 1 | a Smith, Albert V.4 aut |
700 | 1 | a Qu, Liming4 aut |
700 | 1 | a van 't Hof, Femke N. G.4 aut |
700 | 1 | a de Bakker, Paul I. W.4 aut |
700 | 1 | a Baas, Annette F.4 aut |
700 | 1 | a van Rij, Andre4 aut |
700 | 1 | a Tromp, Gerard4 aut |
700 | 1 | a Kuivaniemi, Helena4 aut |
700 | 1 | a Ritchie, Marylyn D.4 aut |
700 | 1 | a Verma, Shefali S.4 aut |
700 | 1 | a Crawford, Dana C.4 aut |
700 | 1 | a Malinowski, Jennifer4 aut |
700 | 1 | a de Andrade, Mariza4 aut |
700 | 1 | a Kullo, Iftikhar J.4 aut |
700 | 1 | a Peissig, Peggy L.4 aut |
700 | 1 | a McCarty, Catherine A.4 aut |
700 | 1 | a Boettinger, Erwin P.4 aut |
700 | 1 | a Gottesman, Omri4 aut |
700 | 1 | a Crosslin, David R.4 aut |
700 | 1 | a Carrell, David S.4 aut |
700 | 1 | a Rasmussen-Torvik, Laura J.4 aut |
700 | 1 | a Pacheco, Jennifer A.4 aut |
700 | 1 | a Huang, Jie4 aut |
700 | 1 | a Timpson, Nicholas J.4 aut |
700 | 1 | a Kettunen, Johannes4 aut |
700 | 1 | a Ala-Korpela, Mika4 aut |
700 | 1 | a Mitchell, Gary F.4 aut |
700 | 1 | a Parsa, Afshin4 aut |
700 | 1 | a Wilkinson, Ian B.4 aut |
700 | 1 | a Gorski, Mathias4 aut |
700 | 1 | a Li, Yong4 aut |
700 | 1 | a Franceschini, Nora4 aut |
700 | 1 | a Keller, Margaux F.4 aut |
700 | 1 | a Ganesh, Santhi K.4 aut |
700 | 1 | a Langefeld, Carl D.4 aut |
700 | 1 | a Bruijn, Lucie4 aut |
700 | 1 | a Brown, Matthew A.4 aut |
700 | 1 | a Evans, David M.4 aut |
700 | 1 | a Baltic, Svetlana4 aut |
700 | 1 | a Ferreira, Manuel A.4 aut |
700 | 1 | a Baurecht, Hansjoerg4 aut |
700 | 1 | a Weidinger, Stephan4 aut |
700 | 1 | a Franke, Andre4 aut |
700 | 1 | a Lubitz, Steven A.4 aut |
700 | 1 | a Mueller-Nurasyid, Martina4 aut |
700 | 1 | a Felix, Janine F.4 aut |
700 | 1 | a Smith, Nicholas L.4 aut |
700 | 1 | a Sudman, Marc4 aut |
700 | 1 | a Thompson, Susan D.4 aut |
700 | 1 | a Zeggini, Eleftheria4 aut |
700 | 1 | a Panoutsopoulou, Kalliope4 aut |
700 | 1 | a Nalls, Mike A.4 aut |
700 | 1 | a Singleton, Andrew4 aut |
700 | 1 | a Polychronakos, Constantin4 aut |
700 | 1 | a Bradfield, Jonathan P.4 aut |
700 | 1 | a Hakonarson, Hakon4 aut |
700 | 1 | a Easton, Douglas F.4 aut |
700 | 1 | a Thompson, Deborah4 aut |
700 | 1 | a Tomlinson, Ian P.4 aut |
700 | 1 | a Dunlop, Malcolm4 aut |
700 | 1 | a Hemminki, Kariu Lund University,Lunds universitet,Allmänmedicin och klinisk epidemiologi,Forskargrupper vid Lunds universitet,Family Medicine and Clinical Epidemiology,Lund University Research Groups4 aut0 (Swepub:lu)med-khk |
700 | 1 | a Morgan, Gareth4 aut |
700 | 1 | a Eisen, Timothy4 aut |
700 | 1 | a Goldschmidt, Hartmut4 aut |
700 | 1 | a Allan, James M.4 aut |
700 | 1 | a Henrion, Marc4 aut |
700 | 1 | a Whiffin, Nicola4 aut |
700 | 1 | a Wang, Yufei4 aut |
700 | 1 | a Chubb, Daniel4 aut |
700 | 1 | a Houlston, Richard S.4 aut |
700 | 1 | a Iles, Mark M.4 aut |
700 | 1 | a Bishop, D. Timothy4 aut |
700 | 1 | a Law, Matthew H.4 aut |
700 | 1 | a Hayward, Nicholas K.4 aut |
700 | 1 | a Luo, Yang4 aut |
700 | 1 | a Nejentsev, Sergey4 aut |
700 | 1 | a Barbalic, Maja4 aut |
700 | 1 | a Crossman, David4 aut |
700 | 1 | a Sanna, Serena4 aut |
700 | 1 | a Soranzo, Nicole4 aut |
700 | 1 | a Markus, Hugh S.4 aut |
700 | 1 | a Wareham, Nicholas J.4 aut |
700 | 1 | a Rader, Daniel J.4 aut |
700 | 1 | a Reilly, Muredach4 aut |
700 | 1 | a Assimes, Themistocles4 aut |
700 | 1 | a Harris, Tamara B.4 aut |
700 | 1 | a Hofman, Albert4 aut |
700 | 1 | a Franco, Oscar H.4 aut |
700 | 1 | a Gudnason, Vilmundur4 aut |
700 | 1 | a Tracy, Russell4 aut |
700 | 1 | a Psaty, Bruce M.4 aut |
700 | 1 | a Farrall, Martin4 aut |
700 | 1 | a Watkins, Hugh4 aut |
700 | 1 | a Hall, Alistair S.4 aut |
700 | 1 | a Samani, Nilesh J.4 aut |
700 | 1 | a Maerz, Winfried4 aut |
700 | 1 | a Clarke, Robert4 aut |
700 | 1 | a Collins, Rory4 aut |
700 | 1 | a Kooner, Jaspal S.4 aut |
700 | 1 | a Chambers, John C.4 aut |
700 | 1 | a Kathiresan, Sekar4 aut |
700 | 1 | a McPherson, Ruth4 aut |
700 | 1 | a Erdmann, Jeanette4 aut |
700 | 1 | a Kastrati, Adnan4 aut |
700 | 1 | a Schunkert, Heribert4 aut |
700 | 1 | a Stefansson, Kari4 aut |
700 | 1 | a Thorsteinsdottir, Unnur4 aut |
700 | 1 | a Walston, Jeremy D.4 aut |
700 | 1 | a Tybjaerg-Hansen, Anne4 aut |
700 | 1 | a Alam, Dewan S.4 aut |
700 | 1 | a Majumder, Abdullah Al Shafi4 aut |
700 | 1 | a Di Angelantonio, Emanuele4 aut |
700 | 1 | a Chowdhury, Rajiv4 aut |
700 | 1 | a Nordestgaard, Borge G.4 aut |
700 | 1 | a Saleheen, Danish4 aut |
700 | 1 | a Thompson, Simon G.4 aut |
700 | 1 | a Danesh, John4 aut |
710 | 2 | a Allmänmedicin och klinisk epidemiologib Forskargrupper vid Lunds universitet4 org |
773 | 0 | t The Lancet Diabetes & Endocrinologyg 3:4, s. 243-253q 3:4<243-253x 2213-8595 |
856 | 4 | u https://portal.research.lu.se/files/3944220/8310668.pdfx primaryx freey FULLTEXT |
856 | 4 | u http://dx.doi.org/10.1016/S2213-8587(15)00034-0x freey FULLTEXT |
856 | 4 8 | u https://lup.lub.lu.se/record/5401427 |
856 | 4 8 | u https://doi.org/10.1016/S2213-8587(15)00034-0 |
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