Metabolic syndrome after transplantation is a major concern following solid organ transplantation (SOT). The CREB-regulated transcription co-activator 2 (CRTC2) regulates glucose metabolism. The effect of CRTC2 polymorphisms on new-onset diabetes after transplantation (NODAT) was investigated in a discovery sample of SOT recipients (n1=197). Positive results were tested for replication in two samples from the Swiss Transplant Cohort Study (STCS, n2=1294 and n3=759). Obesity and other metabolic traits were also tested. Associations with metabolic traits in population-based samples (n4=46’186, n5=123’865, n6>100,000) were finally analyzed. In the discovery sample, CRTC2 rs8450-AA genotype was associated with NODAT, fasting blood glucose and body mass index (Pcorrected<0.05). CRTC2 rs8450-AA genotype was associated with NODAT in the second STCS replication sample (odd ratio (OR)=2.01, P=0.04). In the combined STCS replication samples, the effect of rs8450-AA genotype on NODAT was observed in patients having received SOT from a deceased donor and treated with tacrolimus (n=395, OR=2.08, P=0.02) and in non-kidney transplant recipients (OR=2.09, P=0.02). Moreover, rs8450-AA genotype was associated with overweight or obesity (n=1215, OR=1.56, P=0.02), new-onset hyperlipidemia (n=1007, OR=1.76, P=0.007), and lower high-density lipoprotein-cholesterol (n=1214, β=-0.08, P=0.001). In the population-based samples, a proxy of rs8450G>A was significantly associated with several metabolic abnormalities. CRTC2 rs8450G>A appears to have an important role in the high prevalence of metabolic traits observed in patients with SOT. A weak association with metabolic traits was also observed in the population-based samples.
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Data on glycaemic traits have been contributed by MAGIC investigators and have been downloaded from www.magicinvestigators.org. CBE takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript. This work has been funded in part by the Swiss National Science Foundation (CBE: 324730_144064). LQ and CBE received research support from the Roche Organ Transplantation Research Foundation (#152358701) and the STCS in the past 3 years. ZK was funded by the Swiss National Science Foundation (31003A-143914) and the Leenaards Foundation. This study has been conducted in the framework of the STCS, supported by the Swiss National Science Foundation and the Swiss University Hospitals (G15) and transplant centers.
CBE received honoraria for conferences or teaching CME courses from Advisis, Astra Zeneca, Lundbeck, MSD, Sandoz, Servier and Vifor-Pharma in the past 3 years. He received an unrestricted educational grant from Takeda in the past 3 years. JFD Advisory committees: Bayer, BMS, Gilead Science, Janssen Cilag, Jennerex, Merck, Novartis, Roche. Speaking and teaching: Bayer, Boehringer-Ingelheim, Novartis, Roche. SC received honoraria for teaching CME courses from Astra Zeneca and Lundbeck. The remaining authors have no conflict of interest.
Swiss Transplant Cohort Study Rita Achermann, John-David Aubert, Philippe Baumann, Guido Beldi, Christian Benden, Christoph Berger, Isabelle Binet, Pierre-Yves Bochud, Elsa Boely (Head of local data management), Heiner Bucher, Leo Bühler, Thierry Carell, Emmanuelle Catana, Yves Chalandon, Sabina de Geest, Olivier de Rougemont, Michael Dickenmann, Michel Duchosal, Thomas Fehr, Sylvie Ferrari-Lacraz, Christian Garzoni, Yvan Gasche, Paola Gasche Soccal, Emiliano Giostra, Déla Golshayan, Daniel Good, Karine Hadaya, Christoph Hess, Sven Hillinger, Hans Hirsch, Günther Hofbauer, Uyen Huynh-Do, Franz Immer, Richard Klaghofer, Michael Koller (Head of the data center), Thomas Kuntzen, Bettina Laesser, Roger Lehmann, Christian Lovis, Oriol Manuel, Hans-Peter Marti, Pierre Yves Martin, Pascal Meylan (Head, Biological samples management group), Paul Mohacsi, Isabelle Morard, Philippe Morel, Ulrike Mueller, Nicolas Mueller (Chairman Scientific Committee), Helen Mueller-McKenna, Thomas Müller, Beat Müllhaupt, David Nadal, Gayathri Nair, Manuel Pascual (Executive office), Jakob Passweg, Chantal Piot Ziegler, Juliane Rick, Eddy Roosnek, Anne Rosselet, Silvia Rothlin, Frank Ruschitzka, Urs Schanz, Stefan Schaub, Christian Seiler, Nasser Semmo, Susanne Stampf, Jürg Steiger (Head, Executive Office), Christian Toso, Dimitri Tsinalis, Christian Van Delden (Executive office), Jean-Pierre Venetz, Jean Villard, Madeleine Wick (STCS coordinator), Markus Wilhelm, Patrick Yerly.
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Quteineh, L., Bochud, PY., Golshayan, D. et al. CRTC2 polymorphism as a risk factor for the incidence of metabolic syndrome in patients with solid organ transplantation. Pharmacogenomics J 17, 69–75 (2017). https://doi.org/10.1038/tpj.2015.82
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