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Jeong, Park, Moon, Kim, Shin, Kim, and Lee: The Association of Aldose Reductase Gene Polymorphisms with Neuropathy in Patients with Type 2 Diabetes
Original Article
The Journal of Korean Diabetes Association

The Journal of Korean Diabetes Association 2007; 31(3): 274-283.

Published online: 31 May 2007

DOI: https://doi.org/10.4093/jkda.2007.31.3.274

The Association of Aldose Reductase Gene Polymorphisms with Neuropathy in Patients with Type 2 Diabetes

In-Kyong Jeong, Kyong Soo Park, Min Kyong Moon, Jae Hyeon Kim, Chan Soo Shin, Seong Yeon Kim, Hong Kyu Lee

Department of Internal Medicine, Seoul National University College of Medicine, Korea.

Received 18 October 2006       Accepted 21 March 2007

Copyright © 2007 Korean Diabetes Association

Abstract

Background

Previous studies have suggested that polymorphisms in and around the aldose reductase (AR) gene are associated with the development of diabetic microvascular disease. This study explored the hypothesis that the polymorphisms of the (A-C)n dinucleotide repeat sequence, located at 2.1 kilobase (kb) upstream of the transcription start site of AR gene, modulate the risk of diabetic neuropathy (DN).

Methods

66 patients with DN, 30 without microvascular complications (MC) after 20 years of diabetes, and 87 normal healthy controls were studied. To test highly polymorphic microsatellite marker 2.1 kb upstream of the initiation site of the AR gene, we performed polymerase chain reaction using the primer labeled with fluorescent dye and GeneScan by ABI prism 377 automated DNA sequencer and ABI Genotyper software 2.0.

Results

Seven alleles (Z-6, Z-4, Z-2, Z, Z+2, Z+4 and Z+6) were identified. Z-2 allele was more frequently observed in patients with DN (77.3%) than in those without MC (43.3%, P = 0.007). The subgroup of patients who developed DN within 5 years after the diagnosis of diabetes also had higher frequency of Z-2 allele (91.7%) compared to those without MC (43.3%, P = 0.028). On the contrary, Z+6 allele tended to be more frequent in patients without MC (10.0%) than in those with DN (0%, P = 0.063).

Conclusion

These results support the hypothesis that environmental-genetic interactions may modulate the risk of neuropathy in patients with diabetes. Particularly, the Z-2 allele, in the presence of diabetes, may be associated with the development of DN.

Keywords: Diabetic neuropathy, Microsatellite, polymorphism, (A-C)n dinucleotide

Figures and Tables

Fig. 1
The results of PCR and electrophoresis with 2% agarose gel.
jkda-31-274-g001
Fig. 2
The results of GeneScan by ABI prism 377 automated DNA sequencer and ABI Genotyper software 2.0. The blue-colored peak was the sample labeled FAM and red peakwas internal lane size standard labeled with ROX-500. This example was the homozygote of Z, 23 repeats of (A-C).
jkda-31-274-g002
Table 1
Clinical characteristics of the diabetic patients and the normal control subjects
jkda-31-274-i001

The data are expressed as means ± SD or n. *P < 0.05 vs. normal control subjects, †P < 0.05 vs. diabetic patients with neuropathy.

Table 2
Frequency of the microsatellite alleles at 5-end of aldose reductase gene in the total subjects
jkda-31-274-i002

N, Number of chromosomes.

Table 3
Allele frequency (%) of the microsatellite repeat of aldose reductase gene in patients with type 2 diabetes and normal control subjects
jkda-31-274-i003

Data were expressed by percents. The number in parentheses is the number of n per total number of the group subjects.

*χ2 = 10.7, P = 0.007 between diabetic patients with neuropathy and those without microvascular complication.

†χ2 = 6.8, P = 0.063 between diabetic patients with neuropathy and those without microvascular complication.

Table 4
Allele frequency (%) of the microsatellite repeat of aldose reductase gene in patients who developed diabetic neuropathy within 5 years after the diagnosis of diabetes and in diabetic patients without microvascular complication
jkda-31-274-i004

Data were expressed by percents. The number in parentheses is the number of n per total number of the group subjects

*χ2 = 8.2, P = 0.028.

Table 5
Z-2 genotype frequency of the microsatellite repeat of aldose reductase gene in type 2 diabetic patients with neuropathy and those without microvascular complications
jkda-31-274-i005
Table 6
Z-2 genotype frequency of the microsatellite repeat of aldose reductase gene in patients who developed diabetic neuropathy within 5 years after the diagnosis of diabetes (Group I) and in diabetic patients without microvascular complications (Group II)
jkda-31-274-i006

*χ2 = 6.1, corrected P value = 0.042.

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