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.

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 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.

FIG. 1.

Schematic representation of the UNC13B gene. The structure of UNC13B gene on chromosome 9 is presented with the respective positions of the 39 exons and of the 24 SNPs genotyped (rsID are given in Table 1), as well as the HapMap haplotype blocks (in D′). Arrows at both ends: SNPs selected through sequencing; single arrow: haplotype tagging SNPs selected from Hapmap; arrow with bullet: position of rs13293564, the SNP associated with nephropathy; dashed arrow with bullet: SNPs in complete association with rs13293564 (not typed).

FIG. 2.

ORs for diabetic nephropathy associated with the TT genotype at the rs13293564 polymorphism. Number of control subjects/number of case subjects is shown. □, OR adjusted for age and sex; ▪, OR adjusted for age, sex, smoking, A1C, and proliferative retinopathy.