High-Density Single Nucleotide Polymorphism Genome-Wide Linkage Scan for Susceptibility Genes for Diabetic Nephropathy in Type 1 Diabetes

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.

Uncovering Genes and Regulatory Pathways Related to Urinary Albumin Excretion

“…Comparing these results with previous studies, recently summarized by Garrett et al, 1 we see that the homologous region of the Chr 1 locus has been mapped in a rat cross 7 and a human linkage study, 8 the Chr 4 locus has been mapped in two mouse crosses, B6 ϫ A 3 and B6 ϫ NZM, 4 and the homologous region of the Chr 15 locus has been mapped in a rat cross. 9 This concordance between loci can be used to narrow the interval and exclude genes in the region when we assume that it is the same gene underlying these loci.…”

“…This approach has been used in graphical modeling strategies for QTL and expression-QTL data. 8,19 We applied this strategy to infer causal relationships between candidate genes within the Chr 4 QTL region. In our application, GEX is causal to ACR if the following are satisfied: (1) after conditioning ACR on GEX, the LOD score in the Chr 4 region is reduced below the suggestive level (P Ͻ 0.63, LOD ϭ 2.23) and (2) after conditioning GEX on ACR the LOD score in the Chr 4 region is not reduced below the suggestive level.…”

Successes Achieved and Challenges Ahead in Translating Biomarkers into Clinical Applications

“…Genome-wide linkage scans have suggested several loci (e.g., 1q43, 7q36, 8q21, and 18q23) are candidates for susceptibility (34)(35)(36); however, none of these appear to be a singularly important determinant of diabetic nephropathy. Similarly, the analysis of associations between disease traits and single nucleotide polymorphisms (SNPs) has so far only identified polymorphisms in candidate genes (e.g., angiotensin converting enzyme, aldose reductase, glucose transporter 1, and carnosinase) with small effects (36,37). The current inability to identify genetic biomarkers, which can significantly predict diabetic nephropathy in the general population, may be due to the large variations in racial and genetic backgrounds and the heterogeneity of disease phenotypes in the analysis groups.…”

Identification of a Major Chronic Renal Failure Susceptibility Locus in Mice

“…12 Despite its important clinical relevance and potential effect on morbidity and mortality, there have been very limited data studying this comorbidity in dialysis patients in the United States and only a few worldwide published reports in this population. [13][14][15][16] In this issue, Winkelmayer et al examine the epidemiology (including prevalence, risk factors, and mortality) of atrial fibrillation in patients on maintenance dialysis in the United States over a period of 15 years (1992 to 2006) using the U.S. Renal Data System annual cohorts. The overall prevalence of atrial fibrillation in this patient population exceeded 10% in 2006.…”

“…It is noteworthy that this locus is syntenic with regions on human chromosome 2 and chromosome 3 that have also associated with CKD. 1,2,15,16 The authors also previously reported an important role for the EGF receptor (EGFR) in mediating progressive renal injury. 17 EGFR can be activated by a family of growth factors in addition to EGF, 18 and in FVB/N mice, one of these EGF-like growth factors, TGF-␣, increases in response to progressive renal injury, whereas blocking EGFR activation significantly decreases progressive kidney damage.…”