Publication details

Multilocus approach to the identification of genetic risk factors for diabetic nephropathy in type 2 diabetes

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Year of publication 2004
Type Article in Periodical
Magazine / Source Diabetologia
MU Faculty or unit

Faculty of Medicine

Field Endocrinology, diabetology, metabolism, nutrition
Keywords diabetes; polymorphisms; diabetic nephropathy
Description Background and aims: Set association of selected genetic polymorphisms (40 single nucleotide polymorphisms (SNPs)) in 26 candidate genes on chromosomes 1, 3, 4, 6, 7, 12, 16, 17, 19, 20 and 22 with diabetic nephropathy (DN) was studied in patients with type 2 diabetes mellitus. Products of genes studied were components of renin-angiotensin system, other haemodynamic factors, antioxidant enzymes, cytokines and growth factors, AGE-receptors, extracellular matrix remodelation enzymes and others. Materials and methods: A total of 650 unrelated Caucasian subjects were enrolled into study comprising three groups: diabetics with parallel DN (cases), diabetics without DN (controls 1) and non-diabetics (controls 2). DN diagnosis was based on assessment of albumin excretion rate (AER). Genotypes were detected by means of PCR-based methodology. Set association study was performed to find SNPs jointly associated with disease. Results: An initial comparison of genotype frequencies in case and pooled control individuals furnished P-values below 0.05 for 3 SNPs located on the 6th chromosome, namely 2184A/G in the RAGE gene (Receptor of Advanced Glycation End products), 252A/G in the LTA gene (LymphoToxin-Alpha, formely TNFb) and A16V in the SOD2 gene (Mn superoxiddismutase). Comparing each genotype with the other two combined, the strongest frequency differences between cases and controls were observed for genotype RAGE 2184GG and genotype LTA AA (P=0.03 each). Haplotype analysis furnished highly significant (P<0.0001) results. The highest odds ratio for cases versus controls was 3.58, which was observed for haplotype consisting of the following alleles: RAGE -429C/RAGE 2184G/LTA 252A/SOD2 16A. Conclusions: The preliminary data indicate that certain polymorphisms in genes encoding AGE-receptors, antioxidant enzymes and cytokines could be regarded as contributors to genetic risk factors for DN in type 2 diabetes. Association of these polymorphisms with susceptibility to develop DN and rate of progression and severity of DN in type 1 diabetes is a subject of ongoing study.
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