High-density single nucleotide polymorphism genome-wide linkage scan for susceptibility genes for diabetic nephropathy in type 1 diabetes: discordant sibpair approach

Abstract

Objective: Epidemiological and family studies have demonstrated that susceptibility genes play an important role in the etiology of diabetic nephropathy, defined as persistent proteinuria or end-stage renal disease (ESRD) in type 1 diabetes.

Research design and methods: To efficiently search for genomic regions harboring diabetic nephropathy genes, we conducted a scan using 5,382 informative single nucleotide polymorphisms on 100 sibpairs concordant for type 1 diabetes but discordant for diabetic nephropathy. In addition to being powerful for detecting linkage to diabetic nephropathy, this design allows linkage analysis on type 1 diabetes via traditional affected sibpair (ASP) analysis. In weighing the evidence for linkage, we considered maximum logarithm of odds score (maximum likelihood score [MLS]) values and corresponding allelic sharing patterns, calculated and viewed graphically using the software package SPLAT.

Results: Our primary finding for diabetic nephropathy, broadly defined, is on chromosome 19q (MLS = 3.1), and a secondary peak exists on chromosome 2q (MLS = 2.1). Stratification of discordant sibpairs based on whether disease had progressed to ESRD suggested four tertiary peaks on chromosome 1q (ESRD only), chromosome 20p (proteinuria only), and chromosome 3q (two loci 58 cm apart, one for ESRD only and another for proteinuria only). Additionally, analysis of 130 ASPs for type 1 diabetes confirmed the linkage to the HLA region on chromosome 6p (MLS = 9.2) and IDDM15 on chromosome 6q (MLS = 3.1).

Conclusions: This study identified several novel loci as candidates for diabetic nephropathy, none of which appear to be the sole genetic determinant of diabetic nephropathy in type 1 diabetes. In addition, this study confirms two previously reported type 1 diabetes loci.

FIG. 1.

Chromosome 6 linkage results for 130 sibpairs concordant for type 1 diabetes. The computations and the plots were obtained using SPLAT (16).

FIG. 2.

Linkage results for 100 sibpairs concordant for type 1 diabetes and discordant for nephropathy. Siblings considered unaffected had normoalbuminuria despite a minimum of 10 years duration of diabetes, while affected siblings had proteinuria or ESRD. The computations and the plots were obtained using SPLAT (16).

FIG. 3.

Sharing patterns for ASP (▴) and DSP (•) linkage peaks. Note that both ASP results on chromosome 6 and the DSP peaks for chromosomes 2, 3, 19, and 20 reside within the triangles defined by biological consistency under the respective models. The sharing pattern for the ASP peak on chromosome 5, for example, though comparatively distant from null sharing of 0.25, 0.5, and 0.25, is close to the dotted line defining mean sharing of one-half and is therefore not consistent with true linkage. The computations and the plot were obtained using SPLAT (16).