title: G/T substitution in intron 1 of the UNC13B gene is associated with increased risk of nephropathy in patients with type 1 diabetes.
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.
  
  
  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 x 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 x 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.
authors.affiliation: INSERM, Paris, France, and Pierre and Marie Curie-Paris VI University, Paris, France.
authors.forename: David-Alexandre
authors.initials: DA
authors.lastname: Trégouet
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Groop
authors.forename: Steven
authors.initials: S
authors.lastname: McGinn
authors.forename: Carol
authors.initials: C
authors.lastname: Forsblom
authors.forename: Samy
authors.initials: S
authors.lastname: Hadjadj
authors.forename: Michel
authors.initials: M
authors.lastname: Marre
authors.forename: Hans-Henrik
authors.initials: HH
authors.lastname: Parving
authors.forename: Lise
authors.initials: L
authors.lastname: Tarnow
authors.forename: Ralph
authors.initials: R
authors.lastname: Telgmann
authors.forename: Tiphaine
authors.initials: T
authors.lastname: Godefroy
authors.forename: Viviane
authors.initials: V
authors.lastname: Nicaud
authors.forename: Rachel
authors.initials: R
authors.lastname: Rousseau
authors.forename: Maikki
authors.initials: M
authors.lastname: Parkkonen
authors.forename: Anna
authors.initials: A
authors.lastname: Hoverfält
authors.forename: Ivo
authors.initials: I
authors.lastname: Gut
authors.forename: Simon
authors.initials: S
authors.lastname: Heath
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
authors.forename: Roger
authors.initials: R
authors.lastname: Cox
authors.forename: Gbenga
authors.initials: G
authors.lastname: Kazeem
authors.forename: Martin
authors.initials: M
authors.lastname: Farrall
authors.forename: Dominique
authors.initials: D
authors.lastname: Gauguier
authors.forename: Stefan-Martin
authors.initials: SM
authors.lastname: Brand-Herrmann
authors.forename: François
authors.initials: F
authors.lastname: Cambien
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Nathalie
authors.initials: N
authors.lastname: Vionnet
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000209:etiology / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006367:HeLa Cells; D006801:Humans; D007438:Introns / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D051381:Rats; D012307:Risk Factors
chemical_list: D009419:Nerve Tissue Proteins; C485548:UNC13B protein, human