Abstract
Original language | English |
---|---|
Pages (from-to) | 243-253 |
Journal | The Lancet Diabetes and Endocrinology |
Volume | 3 |
Issue number | 4 |
DOIs | |
Publication status | Published - 2015 |
Externally published | Yes |
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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
C2 - 25726324
VL - 3
SP - 243
EP - 253
JO - Lancet diabetes & endocrinology
JF - Lancet diabetes & endocrinology
SN - 2213-8587
IS - 4
ER -