Aims: Variants in the aldose reductase gene (AKR1B1) have been implicated in the development of diabetic retinopathy and nephropathy, with the most convincing data identifying a (CA)(n) repeat microsatellite allele (Z-2), which has a functional role in gene expression. In this study the association between polymorphisms in the AKR1B1 gene and diabetic neuropathy was investigated.
Methods: The pupillary response to light was used as the major outcome in this study along with abnormal hot thermal threshold. Three hundred and sixty-three adolescents underwent genotyping of the AKR1B1 gene. The microsatellite (CA)(n) repeat was sequenced and two single nucleotide polymorphisms, -106C-->T and -12C-->G, were investigated by restriction fragment length polymorphism.
Results: Seventy-six percent of participants had pupillary abnormalities (45% with two, 15% with three abnormalities). Presence of the Z-2/Z-2 genotype increased the risk nearly three-fold for pupillary abnormalities [odds ratio (OR) 3.02, 95% confidence interval (CI) 1.14, 7.98). The susceptibility genotypes (Z-2/Z-2 with -106C/-106C, Z-2/Z with -106C/-106C or Z/Z with -106C/-106C) were associated with resting pupil diameter abnormalities when compared with the protective genotypes (Z+2/Z+2 or -106T/-106T) (OR 2.83, 95% CI 1.25, 6.41). The combination of Z+2/-106T reduced the risk of abnormal heat discrimination (OR 0.48, 95% CI 0.23, 0.99).
Conclusions: In this study we have shown that Z-2/Z-2 genotype is significantly associated with the development of pupillary abnormality, an early indicator of diabetic autonomic neuropathy, in adolescent Australian patients with Type 1 diabetes.