POLYMORPHISM IN THE 5'-END OF THE ALDOSE REDUCTASE GENE IS STRONGLY ASSOCIATED WITH THE DEVELOPMENT OF DIABETIC NEPHROPATHY IN TYPE-I DIABETES

Recent studies suggest that the gene encoding aldose reductase (ALR2), the enzyme that converts glucose to sorbitol, may confer susceptibili ty to microvascular disease. DNA from 275 British Caucasian patients w ith type I diabetes and 102 normal healthy control patients were typed for a (CA)n dinucleotide repeat polymorphic marker in the 5'-region o f the ALR2 gene using polymorase chain reaction (PCR). A highly signif icant decrease in the frequency of the Z+2 allele was found in patient s with nephropathy (nephropathy group) compared with those with no com plications after a 20-year duration of diabetes (uncomplicated group) (12.7 vs. 38.2%, respectively, chi(2) = 18.6, P < 0.00001); this was a ccompanied by an increase in the Z-2 allele in the nephropathy group ( 32.0 vs. 12.7% in the uncomplicated group), The nephropathy group also had a significant decrease in the Z/Z+2 genotype compared with the un complicated patients (10.7 vs. 44.7%, chi(2) = 16.0, P < 0.0001) and a n increased frequency of the Z/Z-2 genotype. There was no significant association with diabetic retinopathy. These results demonstrate that the ALR2 gene may play a role in susceptibility to diabetic nephropath y; individuals with the Z+2 allele are more than seven times less like ly to develop diabetic renal disease than those without this marker. T his marker may prove valuable in screening for patients with diabetic nephropathy at diagnosis of diabetes.