Susceptibility to diabetic neuropathy in patients with insulin dependent diabetes mellitus is associated with a polymorphism at the 5′ end of the aldose reductase gene

Objectives-There is evidence that the polyol pathway is involved in the pathogenesis of diabetic neuropathy. Aldose reductase (ALR2) is the first and rate limiting enzyme of this pathway and recent studies have suggested that polymorphisms in and around the gene are associated with the development of diabetic microvascular disease. The aim was to examine the role of ALR2 in the susceptibility to diabetic neuropathy in patients with insulin dependent diabetes mellitus (IDDM). Methods-One hundred and fifty nine British white patients with IDDM and 102 normal healthy controls were studied using the polymerase chain reaction to test for a highly polymorphic microsatellite marker 2.1 kilobase (kb) upstream of the initiation site of the ALR2 gene. Results-Seven alleles were detected (Z-6, Z-4, Z-2, Z, Z+2, Z+4, and Z+6). There was a highly significant decrease in the frequency of the Z+2 allele in those patients with overt neuropathy compared with those with no neuropathy after 20 years duration of diabetes (14.1% v 38.2%, chi(2)=17.3, p<0.00001). A similar difference was also found between the neuropathy group and those patients who have had diabetes for< five years with no overt neuropathy (14.1% v 30.2%, chi(2)=9.0, p<0.0025). The neuropathy group also had a significant decrease in the frequency of the Z/Z+2 genotype compared with those patients who have no neuropathy after 20 years duration of diabetes (14.0% v 44.7%, chi(2)=13.0, p<0.0005). Conclusion-These results suggest that the aldose reductase gene is intimately involved in the pathogenesis of diabetic neuropathy.