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Linkage studies have mapped loci for diabetic nephropathy and associated phenotypes on chromosome 3q. We studied 14 plausible candidate genes in the linkage region because of their potential role in vascular complications. In a large-scale study of patients from Denmark, Finland, and France who have type 1 diabetes, 1,057 case and 1,127 control subjects, as well as 532 trios, were investigated for association with diabetic nephropathy. We analyzed 69 haplotype-tagging single nucleotide polymorphisms and nonsynonymous variants that were identified by sequencing. Polymorphisms in three genes, glucose transporter 2 (SLC2A2), kininogen (KNG1), and adiponectin (ADIPOQ), showed nominal association with diabetic nephropathy in single-point analysis. The T-allele of SLC2A2_16459CT was associated with a decreased risk of diabetic nephropathy (odds ratio 0.79 [95% CI 0.66-0.96], P = 0.016), whereas the T-allele of KNG_7965CT and the A-allele of ADIPOQ_prom2GA were associated with increased risk of nephropathy (1.17 [1.03-1.32], P = 0.016; 1.46 [1.11-1.93], P = 0.006, respectively). Analyses of the transmission disequilibrium test showed similar trends only for ADIPOQ_prom2GA with the overtransmission of the A-allele to patients with diabetic nephropathy (1.52 [0.86-2.66], P = NS) and of the G-allele to patients without diabetic nephropathy (0.50 [0.27-0.92], P = 0.026). The overall significance for this variant (nominal P = 0.011) suggests that ADIPOQ might be involved in the development of diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Advanced glycation end-products (AGEs) may play an important role in the pathogenesis and progression of cardiovascular and renal complications of diabetes. Four putative AGE receptors (RAGEs), AGE-R1, AGE-R2, and AGE-R3 have been described. In this study, we scanned the sequence of the genes encoding these AGE receptors in 48 patients with type 1 diabetes and investigated the identified polymorphisms (n = 19) in 199 type 1 diabetic patients with nephropathy and 193 type 1 diabetic patients without nephropathy. Overall, none of the polymorphisms was strongly associated with nephropathy. The minor allele of a polymorphism located in the promoter region of the RAGE gene (C-1152A) conferred a weak protective effect (P < 0.05) and was associated with a longer duration of nephropathy-free diabetes (P = 0.08). [ABSTRACT FROM AUTHOR]

Objective: Genetic and environmental factors modulate the susceptibility to diabetic nephropathy, as initiating and/or progression factors. The objective of the European Rational Approach for the Genetics of Diabetic Complications (EURAGEDIC) study is to identify nephropathy susceptibility genes. We report molecular genetic studies for 127 candidate genes for nephropathy., Research Design and Methods: Polymorphisms were identified through sequencing of promoter, exon, and flanking intron gene regions and a database search. A total of 344 nonredundant SNPs and nonsynonymous variants were tested for association with diabetic nephropathy (persistent albuminuria >/=300 mg/24 h) in a large type 1 diabetes case/control (1,176/1,323) study from three European populations., Results: Only one SNP, rs2281999, located in the UNC13B gene, was significantly associated with nephropathy after correction for multiple testing. Analyses of 21 additional markers fully characterizing the haplotypic variability of the UNC13B gene showed consistent association of SNP rs13293564 (G/T) located in intron 1 of the gene with nephropathy in the three populations. The odds ratio (OR) for nephropathy associated with the TT genotype was 1.68 (95% CI 1.29-2.19) (P = 1.0 x 10(-4)). This association was replicated in an independent population of 412 case subjects and 614 control subjects (combined OR of 1.63 [95% CI 1.30-2.05], P = 2.3 x 10(-5))., Conclusions: We identified a polymorphism in the UNC13B gene associated with nephropathy. UNC13B mediates apopotosis in glomerular cells in the presence of hyperglycemia, an event occurring early in the development of nephropathy. We propose that this polymorphism could be a marker for the initiation of nephropathy. However, further studies are needed to clarify the role of UNC13B in nephropathy.

Objective: Several observational follow-up studies have found that the D allele of the insertion (I)/deletion (D) polymorphism of the ACE gene (ACE/ID) is associated with an increased risk of renal function loss, even during ACE inhibition. Therefore, we investigated the long-term effect of the angiotensin II subtype-1 (AT1) receptor antagonist losartan (100 mg o.d.) on kidney function in II and DD type 1 diabetic patients with diabetic nephropathy., Research Design and Methods: A total of 54 hypertensive type 1 diabetic patients with diabetic nephropathy homozygous for the insertion (n = 26) or the deletion (n = 28) allele were included in the study. After a 4-week washout, the patients received losartan (tablet, 100 mg o.d.) and were followed prospectively with a mean follow-up period of 36 months. Patients and investigators were blinded to ACE genotypes. At baseline, after 2 and 4 months and every 6 months thereafter, glomerular filtration rate (GFR), albuminuria, and 24-h blood pressure were determined., Results: At baseline, GFR, albuminuria, and blood pressure were similar in the two genotype groups, II versus DD: mean (SD), 86 (22) vs. 88 (24) ml. min(-1). 1.73 m(-2); median (interquartile range), 1,134 (598-2,023) vs. 1,451 (893-1,766) mg/24 h; and mean (SD), 156/82 (17/9) vs. 153/80 (17/11) mmHg, respectively. GFR decreased similarly in both genotype groups, versus DD, respectively (P = 0.4): geometric mean (95% CI), 2.9 (2.0-4.2) vs. 3.4 (2.3-5.1) ml. min(-1). year(-1). Albuminuria and arterial blood pressure were significantly reduced during the study; no differences were noted between groups. During follow-up, albuminuria was decreased by 75% (95% CI 59-85) and 73% (56-83) in the II and DD groups, respectively (P < 0.01 vs. baseline). Mean systolic and diastolic blood pressures were 139/74 mmHg (14/8) in both genotype groups during the study (P < 0.01 vs. baseline)., Conclusions: In contrast to previous observational studies with ACE inhibitors, long-term treatment with losartan has similar beneficial renoprotective effects on progression of diabetic nephropathy in hypertensive type 1 diabetic patients with ACE II and DD genotypes.