High-density SNP genome wide linkage scan for susceptibility genes for diabetic nephropathy in type 1 diabetes: Discordant sib-pair approach.

Abstract

Objective. Epidemiological and family studies have demonstrated that susceptibility genes play an important role in the etiology of diabetic nephropathy (DN) defined as persistent proteinuria or end-stage renal disease (ESRD) in type 1 diabetes mellitus (T1DM).

Research Design and Methods. To efficiently search for genomic regions harboring DN genes, we conducted a scan using 5382 informative SNPs on 100 sib pairs concordant for T1DM but discordant for DN. In addition to being powerful for detecting linkage to DN, this design allows linkage analysis on T1DM via traditional affected sib pair (ASP) analysis. In weighing the evidence for linkage, we considered maximum lod score (MLS) values and corresponding allelic sharing patterns, calculated and viewed graphically using the software package Splat.

Results. Our primary finding for DN, broadly defined, is on chromosome 19q (MLS = 3.1) and a secondary peak exists on chromosome 2q (MLS = 2.1). Stratification of DSPs 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 T1DM 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 DN, none of which appear to be the sole genetic determinant of DN in T1DM. In addition this study confirms two previously reported T1DM loci.