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

Aims To investigate association and linkage between DNA sequence variants i n the aldose reductase (AR) gene on chromosome 7q35 and diabetic nephropath y (DN) in Type 1 diabetes mellitus. Methods By sequencing the promoter region and 10 exons in eight DN cases an d eight controls, a frequent bi-allelic polymorphism (C-106T) was discovere d. This polymorphism and the known 5'ALR2 dinucleotide repeat polymorphism were genotyped in unrelated cases with advanced nephropathy (n = 221) and u nrelated 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 e ach). Moreover, the haplotype carrying both risk alleles was in excess in D N cases. In the family study, transmission of risk alleles from heterozygou s parents was consistent with the case-control study, excess transmission i n case-trios and deficient in control-trios. Conclusions Association between DN and two DNA sequence variants in the pro moter region of the AR gene implicates the polyol pathway in the developmen t of kidney complications in Type 1 diabetes mellitus. Further examination of the molecular mechanisms underlying these findings may provide insight i nto the pathogenesis of DN.