A G/T substitution in intron-1 of UNC13B gene is associated with increased risk of nephropathy in patients with type 1 diabetes
- David-Alexandre Trégouet, PhD1,
- Per-Henrik Groop, Pr, MD, PhD2,3,
- Steven McGinn, PhD4,
- Carol Forsblom, MD, PhD2,3,
- Samy Hadjadj, MD, PhD5,6,
- Michel Marre, Pr, MD, PhD7,8,
- Hans-Henrik Parving, Pr, MD, PhD9,
- Lise Tarnow, MD, PhD10,
- Ralph Telgmann, PhD11,
- Tiphaine Godefroy1,
- Viviane Nicaud, Msc1,
- Rachel Rousseau1,
- Maikki Parkkonen3,
- Anna Hoverfält3,
- Ivo Gut, PhD4,
- Simon Heath, PhD4,
- Fumihiko Matsuda, PhD4,
- Roger Cox, PhD12,
- Gbenga Kazeem, PhD13,
- Martin Farrall, PhD13,
- Dominique Gauguier, PhD13,
- Stefan-Martin Brand-Herrmann, PhD11,
- François Cambien, MD, PhD1,
- Mark Lathrop, Pr, PhD4 and
- Nathalie Vionnet, MD, PhD (vionnet{at}cng.fr) For the EURAGEDIC Consortium1
- 1INSERM, UMR S 525, Paris, F-75634 France; Pierre and Marie Curie- Paris VI University, UMR S 525, Paris, F-75634 France
- 2Helsinki University Central Hospital, Department of Medicine, Division of Nephrology, Helsinki, Finland
- 3Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Finland
- 4CEA/Institute of Genomics-National Genotyping Center, Evry, France
- 5CHU Poitiers, Department of Diabetology, Poitiers, France
- 6INSERM U927, CHU Poitiers, Poitiers, France
- 7Bichat University Central Hospital, Department of Diabetology, Paris, France
- 8INSERM U695, Bichat University of Medicine, Paris, France
- 9University hospital of Copenhagen, Rigshospitalet, Department of medical endocrinology, Copenhagen, Denmark
- 10Steno Diabetes Center, Copenhagen, Denmark
- 11Leibniz-Institute for Arteriosclerosis Research, Department of Molecular Genetics of Cardiovascular Disease, University of Muenster, Muenster, Germany
- 12Mammalian Research Council, Mammalian Genetics Unit, Harwell, United Kingdom
- 13Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, United Kingdom
Abstract
Objective: Genetic and environmental factors modulate the susceptibility to diabetic nephropathy (DN), either as initiating and/or progression factors. The objective of the EURAGEDIC study is to identify DN susceptibility genes. We report molecular genetic studies for 127 candidate genes for DN.
Research design and methods: Polymorphisms were identified through sequencing of promoter, exon and flanking intron gene regions and database search. Three-hundred-and-forty-four non-redundant SNPs and non-synonymous variants were tested for association with diabetic nephropathy (persistent albuminuria >300 mg/24h) in a large type 1 diabetes case/control (1176/1323) study from 3 European populations.
Results: Only one SNP, rs2281999 located in UNC13B gene, was significantly associated with DN after correction for multiple testing. Analyses of 21 additional markers fully characterizing the haplotypic variability of the UNC13B gene showed consistent association with SNP rs13293564 (G/T) located in intron 1 of the gene with DN in the 3 populations. The odds ratio (OR) for DN associated with the TT genotype was 1.68 [95%CI, 1.29 – 2.19], p = 1.0 10-4). This association was replicated in an independent population of 412 cases and 614 controls, (combined OR of 1.63 [95%CI, 1.30 – 2.05], p = 2.3 10-5).
Conclusions: We identified a polymorphism in UNC13B gene associated with DN. UNC13B mediates apopotosis in glomerular cells in the presence of hyperglycemia, an event occurring early in the development of DN. We propose that this polymorphism could be a marker for the initiation of DN. However, further studies are needed to clarify the role of UNC13B in DN.
Footnotes
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- Received January 18, 2008.
- Accepted July 8, 2008.
- Copyright © American Diabetes Association
