Novel susceptibility locus at 22q11 for diabetic nephropathy in type 1 diabetes

Abstract

Background: Diabetic nephropathy (DN) affects about 30% of patients with type 1 diabetes (T1D) and contributes to serious morbidity and mortality. So far only the 3q21-q25 region has repeatedly been indicated as a susceptibility region for DN. The aim of this study was to search for new DN susceptibility loci in Finnish, Danish and French T1D families.

Methods and results: We performed a genome-wide linkage study using 384 microsatellite markers. A total of 175 T1D families were studied, of which 94 originated from Finland, 46 from Denmark and 35 from France. The whole sample set consisted of 556 individuals including 42 sib-pairs concordant and 84 sib-pairs discordant for DN. Two-point and multi-point non-parametric linkage analyses were performed using the Analyze package and the MERLIN software. A novel DN locus on 22q11 was identified in the joint analysis of the Finnish, Danish and French families by genome-wide multipoint non-parametric linkage analysis using the Kong and Cox linear model (NPL(pairs) LOD score 3.58). Nominal or suggestive evidence of linkage to this locus was also detected when the three populations were analyzed separately. Suggestive evidence of linkage was found to six additional loci in the Finnish and French sample sets.

Conclusions: This study identified a novel DN locus at chromosome 22q11 with significant evidence of linkage to DN. Our results suggest that this locus may be of importance in European populations. In addition, this study supports previously indicated DN loci on 3q21-q25 and 19q13.

Figure 1. Results of the genome-wide linkage analysis for diabetic nephropathy.

The graphs show values for the Finnish (blue curves), Danish (red curves), French (green curves) and the joint study samples (purple curves) in the multipoint NPL_pairs analysis. For each chromosome, genetic distance (cM) is plotted on the x-axis against the LOD score on the y-axis. Lower horizontal dotted lines represent suggestive evidence (LOD≥1.74) and upper horizontal lines show threshold for significant evidence (LOD≥3.05) of linkage by Feingold et al. criteria.

Figure 2. Results of multipoint linkage analysis on chromosome 22q.

The graphs show the NPL_pairs results on diabetic nephropathy obtained in the joint sample set in the original genome-wide screen (red curve) and after fine-mapping markers were included in the analysis (blue curve).