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Genetic and clinic predictors of new onset diabetes mellitus after transplantation

The Pharmacogenomics Journal volume 19, pages 53–64 (2019)Cite this article

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Abstract

New Onset Diabetes after Transplantation (NODAT) is a frequent complication after solid organ transplantation, with higher incidence during the first year. Several clinical and genetic factors have been described as risk factors of Type 2 Diabetes (T2DM). Additionally, T2DM shares some genetic factors with NODAT. We investigated if three genetic risk scores (w-GRS) and clinical factors were associated with NODAT and how they predicted NODAT development 1 year after transplantation. In both main (n = 725) and replication (n = 156) samples the clinical risk score was significantly associated with NODAT (ORmain: 1.60 [1.36–1.90], p = 3.72*10−8 and ORreplication: 2.14 [1.39–3.41], p = 0.0008, respectively). Two w-GRS were significantly associated with NODAT in the main sample (ORw-GRS 2:1.09 [1.04–1.15], p = 0.001 and ORw-GRS 3:1.14 [1.01–1.29], p = 0.03) and a similar ORw-GRS 2 was found in the replication sample, although it did not reach significance probably due to a power issue. Despite the low OR of w-GRS on NODAT compared to clinical covariates, when integrating w-GRS 2 and w-GRS 3 in the clinical model, the Area under the Receiver Operating Characteristics curve (AUROC), specificity, sensitivity and accuracy were 0.69, 0.71, 0.58 and 0.68, respectively, with significant Likelihood Ratio test discrimination index (p-value 0.0004), performing better in NODAT discrimination than the clinical model alone. Twenty-five patients needed to be genotyped in order to detect one misclassified case that would have developed NODAT 1 year after transplantation if using only clinical covariates. To our knowledge, this is the first study extensively examining genetic risk scores contributing to NODAT development.

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Swiss Transplant Cohort Study

The members of the Swiss Transplant Cohort Study are: Rita Achermann, Patrizia Amico, John-David Aubert, Vanessa Banz, Guido Beldi, Christian Benden, Christoph Berger, Isabelle Binet, Pierre-Yves Bochud, Heiner Bucher, Leo Bühler, Thierry Carell, Emmanuelle Catana, Yves Chalandon, Sabina de Geest, Olivier de Rougemont, Michael Dickenmann, Michel Duchosal, Laure Elkrief, Thomas Fehr, Sylvie Ferrari-Lacraz, Christian Garzoni, Paola Gasche Soccal, Christophe Gaudet, Emiliano Giostra, Déla Golshayan, Karine Hadaya, Jörg Halter, Dominik Heim, Christoph Hess, Sven Hillinger, Hans H. Hirsch, Günther Hofbauer, Uyen Huynh-Do, Franz Immer, Richard Klaghofer, Michael Koller (Head of the data center), Bettina Laesser, Roger Lehmann, Christian Lovis, Oriol Manuel, Hans-Peter Marti, Pierre Yves Martin, Pascal Meylan, (Head, Biological samples management group), Paul Mohacsi, Philippe Morel, Ulrike Mueller, Nicolas J Mueller (Chairman Scientific Committee), Helen Mueller-McKenna (Head of local data management), Antonia Müller, Thomas Müller, Beat Müllhaupt, David Nadal, Manuel Pascual (Executive office), Jakob Passweg, Juliane Rick, Eddy Roosnek, Anne Rosselet, Silvia Rothlin, Frank Ruschitzka, Urs Schanz, Stefan Schaub, Aurelia Schnyder, Christian Seiler, Susanne Stampf, Jürg Steiger (Head, Executive Office), Guido Stirnimann, Christian Toso, Christian Van Delden (Executive office), Jean-Pierre Venetz, Jean Villard, Madeleine Wick (STCS coordinator), Markus Wilhelm, Patrick Yerly.

Funding

This work has been funded in part by the Swiss National Science Foundation (CBE: 324730_144064 and 320030_173211). LQ and CBE received research support from the Roche Organ Transplantation Research Foundation (#152358701) and the Swiss Transplant Cohort Study 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 Swiss Transplant Cohort Study, supported by the Swiss National Science Foundation and the Swiss University Hospitals (G15) and transplant centers.

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Authors and Affiliations

  1. Unit of Pharmacogenetics and Clinical Psychopharmacology, Department of Psychiatry, Lausanne University Hospital, Prilly, Switzerland

    Núria Saigi-Morgui, Lina Quteineh, Severine Crettol & Chin B. Eap

  2. Service of Infectious Diseases, Lausanne University Hospital, Lausanne, Switzerland

    Pierre-Yves Bochud

  3. Institute of Social and Preventive Medicine (IUMSP), Lausanne University Hospital, Lausanne, Switzerland

    Zoltán Kutalik

  4. Swiss Institute of Bioinformatics, Lausanne, Switzerland

    Zoltán Kutalik

  5. Division of Infectious Diseases and Hospital Epidemiology, University Hospital, Zurich, Switzerland

    Nicolas J. Mueller

  6. Service of Nephrology and Transplantation Medicine, Kantonsspital, St Gallen, Switzerland

    Isabelle Binet

  7. Service of Infectious Diseases, University Hospital, Geneva, Switzerland

    Christian Van Delden

  8. Clinic of Transplantationimmunology and Neprhology, University Hospital, Basel, Switzerland

    Jürg Steiger

  9. Swiss Cardiovascular Center Bern, University Hospital, Bern, Switzerland

    Paul Mohacsi

  10. Department of Clinical Pharmacology, University Hospital, Bern, Switzerland

    Jean-francois Dufour

  11. Service of Pulmonary Medicine, University Hospital, Geneva, Switzerland

    Paola M. Soccal

  12. Transplant Center, Lausanne University Hospital, Lausanne, Switzerland

    Manuel Pascual

  13. School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland

    Chin B. Eap

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  1. Núria Saigi-Morgui
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  13. Manuel Pascual
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  14. Chin B. Eap
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the Swiss Transplant Cohort Study

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Correspondence to Chin B. Eap.

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Conflict of interest

C.B.E. received honoraria for conferences or teaching CME courses from Astra Zeneca, Janssen-Cilag, Lundbeck, Merck Sharp & Dohme, Mepha, Otsuka, Servier and Vifor-Pharma in the past 3 years. He received an unrestricted educational grant from Takeda in the past 3 years. J.F.D. 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 declare that they have no competing interests.

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Saigi-Morgui, N., Quteineh, L., Bochud, PY. et al. Genetic and clinic predictors of new onset diabetes mellitus after transplantation. Pharmacogenomics J 19, 53–64 (2019). https://doi.org/10.1038/s41397-017-0001-5

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