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

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.Diabetic nephropathy is the major complication of type 1 diabetes. Clinically, diabetic nephropathy is manifested as persistent proteinuria that frequently progresses to end-stage renal disease (ESRD) (1). While hyperglycemia plays a major role in diabetic nephropathy (1), genetic predisposition has become apparent. Familial aggregation of diabetic nephropathy has been observed in all family studies with multiple type 1 diabetic siblings (2–6). The most comprehensive study, conducted at the Joslin Clinic (4), demonstrated that in comparison with a lifetime diabetic nephropathy risk of 35% among unrelated patients with type 1 diabetes, the risk to a second diabetic sibling increases to 72% or decreases to 25%, depending on whether the first diabetic sibling had diabetic nephropathy. Since familial clustering of glycemic control could not account for this large disparity, a major gene effect was proposed as a plausible explanation (4). To map such a gene, we showed that discordant sibpairs (DSPs) for diabetic nephropathy would be four times as efficient as affected sibpairs (ASPs) (7).Previously, we applied the DSP strategy to a collection of 66 DSPs to test for linkage with genes of the renin-angiotensin system (8). Manual genotyping of microsatellites did not identify any evidence for linkage with AGT (chromosome 1q) and ACE (chromosome 17q); however, we obtained suggestive evidence for linkage with the region on chromosome 3q containing ATR1 (8). Subsequent sequencing of this gene and association studies, however, excluded this gene (8). This report features a larger sample size (100 DSPs from 83 families) and a more stringent definition of diabetic nephropathy.