Novel Susceptibility Locus at 22q11 for Diabetic Nephropathy in Type 1 Diabetes

Abstract

BackgroundDiabetic 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 ResultsWe 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 (NPLpairs 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.ConclusionsThis 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.

The Genetic Landscape of Renal Complications in Type 1 Diabetes

“…This captured heritability could consist of common variants with modest effects, and/or variants of lower frequency, some of them imperfectly tagged by common SNPs. The limited evidence for linkage to DKD 68 and general experience regarding the architecture of other common complex traits, suggest that it is unlikely that DKD risk is dominated by rare variants of large effect, although ultimately sequence based studies will be required for definitive evaluation.…”

Novel Linkage Peaks Discovered for Diabetic Nephropathy in Individuals With Type 1 Diabetes

“…There were also several signals throughout the region including a peak at 25Mb, which occurs on top of the LRRC16A gene, which has been associated with gout (31). Several studies including our previous linkage analysis showed a linkage peak at chromosome 6p21 (8). As this linkage peak occurred on the HLA region and the concordant and discordant sibling pairs showed similar haplotype inheritance pattern, it was presumed that the peak originated from the genetic risk of T1D, and not from DN.…”

“…Several previous linkage studies found a genome-wide significant or suggestive linkage peak on chromosome 3q in Finnish and other populations (7). More recently, a significant linkage peak was found on chromosome 22 in Danish, Finnish and French sibling pairs (8). However, these linkage peaks do not occur in overlapping regions with GWAS findings, and the genetic background of the findings remains largely unclear.…”

Analysis of coding variants identified from exome sequencing resources for association with diabetic and non-diabetic nephropathy in African Americans

“…SNPs in genes on chromosome 22 were notably represented. The importance of chromosome 22 in African American nephropathy has been established by various reports in non-diabetic (Behar et al 2010; Freedman et al 2009b; Freedman et al 2010; Freedman et al 2009c; Freedman et al 2012; Genovese et al 2010; Kao et al 2008; Kopp et al 2008; O’Seaghdha et al 2011; Pattaro et al 2009), T2D-associated (Cooke et al 2012; Freedman et al 2009a; McDonough et al 2011), and type 1 diabetic nephropathy (Wessman et al 2011). With the established importance of chromosome 22, many of the genes targeted in this study, including APOL3, APOL2, APOL1, LIMK2, and MYH9 , were from this chromosome.…”