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

Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.
Diabetes (Impact Factor: 8.1). 07/2008; 57(9):2519-26. DOI: 10.2337/db07-1086
Source: PubMed


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.
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.
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).
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.

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Available from: Luís Henrique Canani, Dec 20, 2013
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    • "MHC class II and HLA alleles polymorphism have been associated with renal diseases in diabetes type 1 nephropathy [40], [41] or anti-glomerular basement membrane disease [42]. The critiques of these genetic studies focused on single nucleotide polymorphism have been softened by recent Genome wide Association Studies. "
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    • "Genetic studies have found evidence for linkage to nephropathy at a number of chromosome loci including 2q, 3q22 and 19q [11,12]. While no consistently replicated genetic associations have been identified, various candidate gene associations in diabetic nephropathy in type 1 diabetes (T1D) have been proposed, such as the SNP rs13293564 G/T substitution in intron 1 of UNC13B [13], and SOD1 SNPs [14]. "
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    • "With the approaches of genome wide scan and linkage analyses, researchers have searched for the linkage to DN along chromosomes. The linkage to DN in chromosome 3q has been evidenced repeatedly in many ethnic groups, and indicated that there reside the susceptibility and/or resistant genes for DN in this chromosomal arm [7-13]. The adiponectin (ADIPOQ) gene is located in chromosome 3q27. "
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