Aldose reductase gene polymorphisms and susceptibility to diabetic nephropathy in Type 1 diabetes mellitus

Aims To investigate association and linkage between DNA sequence variants in the aldose reductase (AR) gene on chromosome 7q35 and diabetic nephropathy (DN) in Type 1 diabetes mellitus. Methods By sequencing the promoter region and 10 exons in eight DN cases and eight controls, a frequent bi-allelic polymorphism (C-106T) was discovered. This polymorphism and the known 5'ALR2 dinucleotide repeat polymorphism were genotyped in unrelated cases with advanced nephropathy (n = 221) and unrelated controls with normoalbuminuria (n = 193). For a family based study, 166 case-trios (case and both parents) and 83 control-trios (control and both parents) were also genotyped. Results In the case-control study, carriers of the Z-2 allele of the 5'ALR2 polymorphism had a significantly higher risk of DN than non-carriers (odds ratios: 1.6 for heterozygotes and 2.1 for homozygotes, P < 0.05 for each). The same was true for carriers of the T allele of the C-106T polymorphism (odds ratios: 1.6 for heterozygotes and 1.9 for homozygotes, P < 0.05 for each). Moreover, the haplotype carrying both risk alleles was in excess in DN cases. In the family study, transmission of risk alleles from heterozygous parents was consistent with the case-control study, excess transmission in case-trios and deficient in control-trios. Conclusions Association between DN and two DNA sequence variants in the promoter region of the AR gene implicates the polyol pathway in the development of kidney complications in Type 1 diabetes mellitus. Further examination of the molecular mechanisms underlying these findings may provide insight into the pathogenesis of DN.