This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shah, V. O. Articles by Zager, P. G. Search for Related Content PubMed PubMed Citation Articles by Shah, V. O. Articles by Zager, P. G.

Z-2 Microsatellite Allele Is Linked to Increased Expression of the Aldose Reductase Gene in Diabetic Nephropathy¹

Departments of Biochemistry (V.O.S., J.K.G., D.L.V.J.), Internal Medicine (V.O.S., Y.S., R.I.D., M.Y., R.P.E., P.G.Z.), and Family and Community Medicine (C.S.), University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131; Dialysis Clinic, Inc. (J.N.), Nashville, Tennessee 37203; and the Department of Medicine, Istituto Scientifico H San Raffaele (M.S., S.V.), 20132 Milan, Italy

Address all correspondence and requests for reprints to: Philip G. Zager, M.D., Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131. E-mail: pzag{at}unm.edu

Epidemiological studies support the hypothesis that genetic factors modulate the risk for diabetic nephropathy (DN). Aldose reductase (ALDR1), the rate-limiting enzyme in the polyol pathway, is a potential candidate gene. The present study explores the hypothesis that polymorphisms of the (A-C)n dinucleotide repeat sequence, located 2.1 kb upstream of the transcription start site, modulate ALDR1 gene expression and the risk for DN.

We conducted studies at two different institutions, the University of New Mexico Health Sciences Center (UNMHSC), and the Istituto Scientifico H San Raffaele (HSR). There were four groups of volunteers at UNMHSC: group I, normal subjects; group II, patients with insulin-dependent diabetes mellitus (IDDM) without DN; group III, IDDM with DN; and group IV, nondiabetics with kidney disease. At HSR we studied volunteers in groups I, II, and III. ALDR1 genotype was assessed by PCR and fluorescent sequencing of the (A-C)n repeat locus, and ALDR1 messenger ribonucleic acid (mRNA) was measured by ribonuclease protection assay in peripheral blood mononuclear cells.

At UNMHSC we identified 10 alleles ranging from Z-10 to Z+8. The prevalence of the Z-2 allele among IDDM patients was increased in those with DN. Sixty percent of group III and 22% of group II were homozygous for Z-2. Moreover, 90% and 67% of groups III and II, respectively, had 1 or more copy of Z-2. In contrast, among nondiabetics, 19% of group IV and 3% of group I were homozygous for Z-2, and 69% and 32%, respectively, had 1 copy or more of Z-2. Among diabetics, homozygosity for the Z-2 allele was associated with renal disease [odds ratio (OR), 5.25; 95% confidence interval, 1.71–17.98; P = 0.005]. ALDR1 mRNA levels were higher in patients with DN (group III; 0.113 ± 0.050) than in group I (0.068 ± 0.025), group II (0.042 ± 0.020), or group IV (0.015 ± 0.011; P < 0.01). Among diabetics, ALDR1 mRNA levels were higher in Z-2 homozygotes (0.098 ± 0.06) and Z-2 heterozygotes (0.080 ± 0.04) than in patients with no Z-2 allele (0.043 ± 0.02; P < 0.05). In contrast, among nondiabetics, ALDR1 mRNA levels in Z-2 homozygotes (0.034 ± 0.04) and Z-2 heterozygotes (0.038 ± 0.03) were similar to levels in patients without a Z-2 allele (0.047 ± 0.03; P = NS).

At HSR we identified eight alleles ranging from Z-12 to Z+2. The prevalence of the Z-2 allele was higher in group III than in group II. In group III, 43% of the patients were homozygous for Z-2, and 81% had one copy or more of the Z-2 allele. In contrast, in group II, 4% were homozygous for Z-2, and 36% had one copy or more of the Z-2 allele. IDDM patients homozygous for Z-2 had an increased risk for DN compared with those lacking the Z-2 allele (OR, 18; 95% confidence interval, 2–159). IDDM patients who had one copy or more of Z-2 had increased risk (OR, 7.5; 95% confidence interval, 1.9–29.4) for DN compared with those without the Z-2 allele.

These results support our hypothesis that environmental-genetic interactions modulate the risk for DN. Specifically, the Z-2 allele, in the presence of diabetes and/or hyperglycemia, is associated with increased ALDR1 expression. This interaction may explain the observed association between the Z-2 allele and DN.

This article has been cited by other articles:

				W.-Y. So, Y. Wang, M. C.Y. Ng, X. Yang, R. C.W. Ma, V. Lam, A. P.S. Kong, P. C.Y. Tong, and J. C.N. Chan Aldose Reductase Genotypes and Cardiorenal Complications: An 8-year prospective analysis of 1,074 type 2 diabetic patients Diabetes Care, November 1, 2008; 31(11): 2148 - 2153. [Abstract] [Full Text] [PDF]

				M. Xu, X. Chen, L. Yan, H. Cheng, and W. Chen Association between (AC)n dinucleotide repeat polymorphism at the 5'-end of the aldose reductase gene and diabetic nephropathy: a meta-analysis J. Mol. Endocrinol., May 1, 2008; 40(5): 243 - 251. [Abstract] [Full Text] [PDF]

				C. Granier, K. Makni, L. Molina, B. Jardin-Watelet, H. Ayadi, and F. Jarraya Gene and protein markers of diabetic nephropathy Nephrol. Dial. Transplant., March 1, 2008; 23(3): 792 - 799. [Full Text] [PDF]

				K. Thamotharampillai, A. K.F. Chan, B. Bennetts, M. E. Craig, J. Cusumano, M. Silink, P. J. Oates, and K. C. Donaghue Decline in Neurophysiological Function After 7 Years in an Adolescent Diabetic Cohort and the Role of Aldose Reductase Gene Polymorphisms. Diabetes Care, September 1, 2006; 29(9): 2053 - 2057. [Abstract] [Full Text] [PDF]

				B. F. Schrijvers, A. S. De Vriese, and A. Flyvbjerg From Hyperglycemia to Diabetic Kidney Disease: The Role of Metabolic, Hemodynamic, Intracellular Factors and Growth Factors/Cytokines Endocr. Rev., December 1, 2004; 25(6): 971 - 1010. [Abstract] [Full Text] [PDF]

				H.-L. Zhao, P. C.Y. Tong, F. M.M. Lai, B. Tomlinson, and J. C.N. Chan Association of Glomerulopathy With the 5'-End Polymorphism of the Aldose Reductase Gene and Renal Insufficiency in Type 2 Diabetic Patients Diabetes, November 1, 2004; 53(11): 2984 - 2991. [Abstract] [Full Text] [PDF]

				K. Sivenius, J. Pihlajamaki, J. Partanen, L. Niskanen, M. Laakso, and M. Uusitupa Aldose Reductase Gene Polymorphisms and Peripheral Nerve Function in Patients With Type 2 Diabetes Diabetes Care, August 1, 2004; 27(8): 2021 - 2026. [Abstract] [Full Text] [PDF]

				A. D. Hodgkinson, T. Bartlett, P. J. Oates, B. A. Millward, and A. G. Demaine The Response of Antioxidant Genes to Hyperglycemia Is Abnormal in Patients With Type 1 Diabetes and Diabetic Nephropathy Diabetes, March 1, 2003; 52(3): 846 - 851. [Abstract] [Full Text] [PDF]

				H. Gallagher and P. A Andrews What is diabetic renal disease? The British Journal of Diabetes & Vascular Disease, March 1, 2002; 2(2): 96 - 100. [Abstract] [PDF]

				A. Demaine, D. Cross, and A. Millward Polymorphisms of the Aldose Reductase Gene and Susceptibility to Retinopathy in Type 1 Diabetes Mellitus Invest. Ophthalmol. Vis. Sci., December 1, 2000; 41(13): 4064 - 4068. [Abstract] [Full Text]

				B. Isermann, S. Schmidt, A. Bierhaus, S. Schiekofer, V. Borcea, R. Ziegler, P. P. Nawroth, and E. Ritz (CA)n Dinucleotide repeat polymorphism at the 5'-end of the aldose reductase gene is not associated with microangiopathy in Caucasians with long-term diabetes mellitus 1 Nephrol. Dial. Transplant., June 1, 2000; 15(6): 918 - 920. [Full Text] [PDF]