G/T Substitution in Intron 1 of the UNC13B Gene Is Associated With Increased Risk of Nephropathy in Patients With Type 1 Diabetes David-Alexandre Trégouet 1 , Per-Henrik Groop 2 3 , Steven McGinn 4 , Carol Forsblom 2 3 , Samy Hadjadj 5 6 , Michel Marre 7 8 , Hans-Henrik Parving 9 , Lise Tarnow 10 , Ralph Telgmann 11 , Tiphaine Godefroy 1 , Viviane Nicaud 1 , Rachel Rousseau 1 , Maikki Parkkonen 3 , Anna Hoverfält 3 , Ivo Gut 4 , Simon Heath 4 , Fumihiko Matsuda 4 , Roger Cox 12 , Gbenga Kazeem 13 , Martin Farrall 13 , Dominique Gauguier 13 , Stefan-Martin Brand-Herrmann 11 , François Cambien 1 , Mark Lathrop 4 , Nathalie Vionnet 1 and for the EURAGEDIC Consortium 1 INSERM, Paris, France, and Pierre and Marie Curie-Paris VI University, Paris, France 2 Helsinki University Central Hospital, Department of Medicine, Division of Nephrology, Helsinki, Finland 3 Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum, Helsinki, Finland 4 CEA/Institute of Genomics-National Genotyping Center, Evry, France 5 CHU Poitiers, Department of Diabetology, Poitiers, France 6 INSERM U927, CHU Poitiers, Poitiers, France 7 Assistance Publique des Hôpitaux de Paris, Centre Hospitalier Universitaire Bichat-Claude Bernard, Paris, France 8 Université Paris, INSERM U695, Paris, France 9 University Hospital of Copenhagen, Rigshospitalet, Department of Medical Endocrinology, Copenhagen, Denmark 10 Steno Diabetes Center, Copenhagen, Denmark 11 Leibniz Institute for Arteriosclerosis Research, Department of Molecular Genetics of Cardiovascular Disease, University of Muenster, Muenster, Germany 12 Mammalian Research Council, Mammalian Genetics Unit, Harwell, U.K 13 Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, U.K Corresponding author: Nathalie Vionnet, vionnet{at}cng.fr Abstract OBJECTIVE— Genetic and environmental factors modulate the susceptibility to diabetic nephropathy, as initiating and/or progression factors. The objective of the European Rational Approach for the Genetics of Diabetic Complications (EURAGEDIC) study is to identify nephropathy susceptibility genes. We report molecular genetic studies for 127 candidate genes for nephropathy. RESEARCH DESIGN AND METHODS— Polymorphisms were identified through sequencing of promoter, exon, and flanking intron gene regions and a database search. A total of 344 nonredundant SNPs and nonsynonymous variants were tested for association with diabetic nephropathy (persistent albuminuria ≥300 mg/24 h) in a large type 1 diabetes case/control (1,176/1,323) study from three European populations. RESULTS— Only one SNP, rs2281999, located in the UNC13B gene, was significantly associated with nephropathy after correction for multiple testing. Analyses of 21 additional markers fully characterizing the haplotypic variability of the UNC13B gene showed consistent association of SNP rs13293564 (G/T) located in intron 1 of the gene with nephropathy in the three populations. The odds ratio (OR) for nephropathy 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 case subjects and 614 control subjects (combined OR of 1.63 95% CI 1.30–2.05, P = 2.3 × 10 −5 ). CONCLUSIONS— We identified a polymorphism in the UNC13B gene associated with nephropathy. UNC13B mediates apopotosis in glomerular cells in the presence of hyperglycemia, an event occurring early in the development of nephropathy. We propose that this polymorphism could be a marker for the initiation of nephropathy. However, further studies are needed to clarify the role of UNC13B in nephropathy. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 15 July 2008. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted July 8, 2008. Received January 18, 2008. DIABETES