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      C-106T Polymorphism in Promoter of Aldose Reductase Gene Is a Risk Factor for Diabetic Nephropathy in Type 2 Diabetes Patients with Poor Glycaemic Control

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          Background: Excessive flux through the polyol pathway has long been thought to be involved in the pathogenesis of diabetic microvascular complications. Aldose reductase (AR) is the first and rate-limiting enzyme in the pathway that catalyses the reduction of glucose to sorbitol. A frequent C-106T polymorphism in the promoter of the AR gene has been described, which may change the expression of the gene. The aim of the study was to examine if the C-106T polymorphism was associated with diabetic nephropathy. Material and Methods: We collected 444 patients with type 2 diabetes and divided them into three groups according to the renal status: 162 patients with normoalbuminuria, 153 with microalbuminuria and 129 with persistent proteinuria. Each subject was genotyped for the C-106 polymorphism using the PCR-based RFLP protocol. Results: When the whole study population was analysed, no distortion in the genotype frequency among the study groups was observed. When we stratified the study population by HbA1c we found that in patients with HbA1c ≧9% (median) the CT and TT genotypes were more frequent in patients with diabetic nephropathy (proteinuria and microalbuminuria) than those with normoalbuminuria (OR 2.04, 95% CI 1.12–3.74). Conclusion: The C-106T polymorphism in the AR gene is a risk factor for development of diabetic nephropathy in type 2 diabetes in patients with poor glycaemic control.

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          Most cited references 16

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          A novel polymorphism in the aldose reductase gene promoter region is strongly associated with diabetic retinopathy in adolescents with type 1 diabetes.

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            Retinal capillaries: basement membrane thickening by galactosemia prevented with aldose reductase inhibitor.

            A twofold thickening of capillary basement membranes of rat retinas resulting from dietary galactose was prevented by sorbinil, an inhibitor of aldose reductase. Since the basement membrane thickening was ultrastructurally similar to that typical of diabetic retinopathy, it may indicate changes in vessel permeability and susceptibility to hemorrhage. Galactosemic rats should be useful models for studying basement membrane-related complications of diabetes and for examining the potential biochemical regulation of basement membrane synthesis by aldose reductase inhibitors.
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              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 susceptibility to microvascular disease. DNA from 275 British Caucasian patients with type I diabetes and 102 normal healthy control patients were typed for a (CA)n dinucleotide repeat polymorphic marker in the 5'-region of the ALR2 gene using polymorase chain reaction (PCR). A highly significant decrease in the frequency of the Z+2 allele was found in patients with nephropathy (nephropathy group) compared with those with no complications after a 20-year duration of diabetes (uncomplicated group) (12.7 vs. 38.2%, respectively, chi2 = 18.6, P < 0.00001); this was accompanied 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 uncomplicated patients (10.7 vs. 44.7%, chi2 = 16.0, P < 0.0001) and an 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 nephropathy; individuals with the Z+2 allele are more than seven times less likely to develop diabetic renal disease than those without this marker. This marker may prove valuable in screening for patients with diabetic nephropathy at diagnosis of diabetes.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                March 2005
                20 January 2005
                : 99
                : 3
                : e63-e67
                Department and Clinic of Internal Medicine, Diabetology and Nephrology, Silesian School of Medicine, Zabrze, Poland
                83209 Nephron Exp Nephrol 2005;99:e63–e67
                © 2005 S. Karger AG, Basel

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