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CD2AP is associated with end-stage renal disease in patients with type 1 diabetes

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Abstract

CD2-associated protein (CD2AP) is essential for podocyte function. CD2AP mutations have been found in patients with focal segmental glomerulosclerosis, a disease histologically resembling diabetic nephropathy and often progressing to end-stage renal disease (ESRD). We hypothesised that variations in the CD2AP gene may contribute to susceptibility to glomerular injury in diabetes and investigated if single-nucleotide polymorphisms (SNPs) in CD2AP are associated with diabetic nephropathy in patients with type 1 diabetes. The discovery cohort consisted of 2,251 Finnish patients with type 1 diabetes. SNPs were selected from the HapMap database to cover the CD2AP gene. The associations between genotyped SNPs and diabetic nephropathy or ESRD were analysed with the chi-squared test and logistic regression. Three SNPs were selected for replication in cohorts from Denmark, Italy, the United Kingdom and Ireland. None of the 15 successfully genotyped SNPs were associated with diabetic nephropathy when compared to patients with normal albumin excretion rate. However, when genotype frequencies in patients with ESRD were compared with all other patients, two CD2AP SNPs, rs9369717 and rs9349417, were found to be associated with ESRD. The meta-analysis of the original and two additional European cohorts resulted in significant p values <0.01 for these SNPs. A third SNP, rs6936632, was suggestively associated with ESRD in the Finnish patients and in the meta-analysis of four cohorts. CD2AP gene variants may contribute to susceptibility to ESRD in patients with type 1 diabetes.

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Acknowledgments

We thank Maikki Parkkonen for accomplished technical assistance and advice. We thank all the persons who participated in the study and gratefully acknowledge all the physicians and nurses involved in the recruitment of participants in the FinnDiane study (ESM 3). The Warren 3/U.K. GoKinD Study Group was jointly funded by Diabetes UK and the Juvenile Diabetes Research Foundation and includes the following individuals: A.P. Maxwell, A.J. McKnight, D.A. Savage (Belfast); J. Walker (Edinburgh); S. Thomas, G.C. Viberti (London); A.J.M. Boulton (Manchester); S. Marshall (Newcastle); A.G. Demaine and B.A. Millward (Plymouth); Professor S.C. Bain (Swansea). This study was financially supported by the Academy of Finland (121248, 131255, 218021, 134379), the European Research Council (242820), the Diabetes Research Foundation, the Foundation for Paediatric Research, the National Graduate School of Clinical Investigation, Folkhälsan Research Foundation, Wilhelm and Else Stockmann Foundation, Kyllikki and Uolevi Lehikoinen Foundation, the Finnish Cultural Foundation, Liv och Hälsa Foundation and Finnish Medical Society (Finska Läkaresällskapet). MS was supported by the Sectoral Operational Programme Human Resources Development (SOP HRD), financed from the European Social Fund and by the Romanian Government under the contract number POSDRU/89/1.5/S/64109. Genotyping of the UK-ROI samples was supported by the Northern Ireland Kidney Research Fund. GL received a PhD studentship jointly funded by Kidney Research UK and Diabetes UK.

Conflict of interest

PHG has received honorariums from Boehringer Ingelheim, Novartis, Eli Lilly, Genzyme, MSD and Novo Nordisk, research grants from Eli Lilly and Roche and is a member of advisory boards in Boehringer Ingelheim and Novartis. The present study is not financially supported by a pharmaceutical company.

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Authors and Affiliations

  1. Department of Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland

    Mervi E. Hyvönen & Sanna Lehtonen

  2. Children’s Hospital, University of Helsinki, Helsinki, Finland

    Mervi E. Hyvönen

  3. Folkhälsan Institute of Genetics, Folkhälsan Research Center, University of Helsinki, PO Box 63, 00014, Helsinki, Finland

    Pekka Ihalmo, Niina Sandholm, Monica Stavarachi, Carol Forsblom & Per-Henrik Groop

  4. Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland

    Niina Sandholm, Carol Forsblom & Per-Henrik Groop

  5. Department of Biomedical Engineering and Computational Science, Aalto University, Espoo, Finland

    Niina Sandholm

  6. Nephrology Research, Centre for Public Health, Queen’s University of Belfast, Belfast, UK

    Amy Jayne McKnight, Gareth Lewis & Alexander P. Maxwell

  7. Steno Diabetes Center, Gentofte, Denmark

    Maria Lajer & Lise Tarnow

  8. Complications of Diabetes Unit, Division of Metabolic and Cardiovascular Sciences, San Raffaele Scientific Institute, Milan, Italy

    Anna Maestroni, Silvia Maestroni & Gianpaolo Zerbini

  9. Faculty of Health, University of Aarhus, Aarhus, Denmark

    Lise Tarnow

  10. Department of Medical Endocrinology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    Hans-Henrik Parving

  11. Baker IDI Heart and Diabetes Institute, Melbourne, Australia

    Per-Henrik Groop

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  1. Mervi E. Hyvönen
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Correspondence to Per-Henrik Groop.

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Communicated by Antonio Secchi.

This study is conducted on behalf of the FinnDiane Study Group.

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Hyvönen, M.E., Ihalmo, P., Sandholm, N. et al. CD2AP is associated with end-stage renal disease in patients with type 1 diabetes. Acta Diabetol 50, 887–897 (2013). https://doi.org/10.1007/s00592-013-0475-9

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