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

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Fältnamn	Indikatorer	Metadata
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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Av författaren/redakt...: Freitag, Daniel ...; Butterworth, Ada ...; Willeit, Peter; Howson, Joanna M ...; Burgess, Stephen; Kaptoge, Stephen; visa fler...; Young, Robin; Ho, Weang Kee; Wood, Angela M.; Sweeting, Michae ...; 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, Gu ...; Zeng, Lingyao; Kessler, Thorste ...; Nikpay, Majid; Do, Ron; Zhang, Weihua; Hopewell, Jemma ...; Kleber, Marcus; Delgado, Graciel ...; Nelson, Christop ...; Goel, Anuj; Bis, Joshua C.; Dehghan, Abbas; Ligthart, Symen; Smith, Albert V.; Qu, Liming; van 't Hof, Femk ...; de Bakker, Paul ...; Baas, Annette F.; van Rij, Andre; Tromp, Gerard; Kuivaniemi, Hele ...; Ritchie, Marylyn ...; Verma, Shefali S ...; Crawford, Dana C ...; Malinowski, Jenn ...; de Andrade, Mari ...; Kullo, Iftikhar ...; Peissig, Peggy L ...; McCarty, Catheri ...; Boettinger, Erwi ...; Gottesman, Omri; Crosslin, David ...; Carrell, David S ...; Rasmussen-Torvik ...; Pacheco, Jennife ...; Huang, Jie; Timpson, Nichola ...; Kettunen, Johann ...; Ala-Korpela, Mik ...; Mitchell, Gary F ...; Parsa, Afshin; Wilkinson, Ian B ...; Gorski, Mathias; Li, Yong; Franceschini, No ...; Keller, Margaux ...; Ganesh, Santhi K ...; Langefeld, Carl ...; Bruijn, Lucie; Brown, Matthew A ...; Evans, David M.; Baltic, Svetlana; Ferreira, Manuel ...; Baurecht, Hansjo ...; Weidinger, Steph ...; Franke, Andre; Lubitz, Steven A ...; Mueller-Nurasyid ...; Felix, Janine F.; Smith, Nicholas ...; Sudman, Marc; Thompson, Susan ...; Zeggini, Elefthe ...; Panoutsopoulou, ...; Nalls, Mike A.; Singleton, Andre ...; Polychronakos, C ...; Bradfield, Jonat ...; Hakonarson, Hako ...; Easton, Douglas ...; Thompson, Debora ...; Tomlinson, Ian P ...; Dunlop, Malcolm; Hemminki, Kari; Morgan, Gareth; Eisen, Timothy; Goldschmidt, Har ...; Allan, James M.; Henrion, Marc; Whiffin, Nicola; Wang, Yufei; Chubb, Daniel; Houlston, Richar ...; Iles, Mark M.; Bishop, D. Timot ...; Law, Matthew H.; Hayward, Nichola ...; Luo, Yang; Nejentsev, Serge ...; Barbalic, Maja; Crossman, David; Sanna, Serena; Soranzo, Nicole; Markus, Hugh S.; Wareham, Nichola ...; Rader, Daniel J.; Reilly, Muredach; Assimes, Themist ...; Harris, Tamara B ...; Hofman, Albert; Franco, Oscar H.; Gudnason, Vilmun ...; Tracy, Russell; Psaty, Bruce M.; Farrall, Martin; Watkins, Hugh; Hall, Alistair S ...; Samani, Nilesh J ...; Maerz, Winfried; Clarke, Robert; Collins, Rory; Kooner, Jaspal S ...; Chambers, John C ...; Kathiresan, Seka ...; McPherson, Ruth; Erdmann, Jeanett ...; Kastrati, Adnan; Schunkert, Herib ...; Stefansson, Kari; Thorsteinsdottir ...; Walston, Jeremy ...; Tybjaerg-Hansen, ...; Alam, Dewan S.; Majumder, Abdull ...; Di Angelantonio, ...; Chowdhury, Rajiv; Nordestgaard, Bo ...; Saleheen, Danish; Thompson, Simon ...; Danesh, John; visa färre...

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