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Polymorphisms in the Mn-SOD and EC-SOD Genes and Their Relationship to Diabetic Neuropathy in Type 1 Diabetes Mellitus
Authors: Dimitry A Chistyakov, Kirill V Savost'anov, Elena V Zotova, Valery V Nosikov, JV Hunt, SP Wolff, PA Low, KK Nickander, HJ Tritschler, M Zhu, DC Spink, B Yan, S Bank, AP DeCaprio, NE Cameron, MA Cotter, M. Nagamatsu, KK Nickander, JD Schmelzer, A Raya, DA Wittrock, H Tritschler, PA Low, PS Van Dam, BS Van Asbeck, B Bravenboer, JF Van Oirschot, JJ Marx, WH Gispen, A Martinez-Blasco, F Bosch-Morell, C Trenor, FJ Romero, H Yan, JJ Harding, S Shimoda-Matsubayashi, H Matsumine, T Kobayashi, Y Nakagawa-Hattori, Y Shimizu, Y Mizino, JS Rosenblum, NB Gilula, RA Lerner, H Hori, O Ohmori, T Shinkai, H Kojima, C Okano, T Suzuki, J Nakamura, GF Van Landeghem, P Tabatabaie, G Beckman, L Beckman, PM Andersen, S Hiroi, H Harada, H Nishi, M Satoh, R Nagai, A Kimura, GE Borgstahl, HE Parge, MJ Hickey, MJ Johnson, M Boissinot, RA Hallewell, JR Lepock, DE Cabelli, JA Tainer, H Checkoway, FM Farin, P Costa-Mallen, SC Kirchner, LG Costa, EM Grasbon-Frodl, S Kosel, O Riess, U Muller, P Mehraein, MB Graeber, J Sandstrom, P Nilsson, K Karlsson, SL Marklund, H Yamada, Y Yamada, T Adachi, H Goto, N Ogasawara, A Futenma, M Kitano, K Hirano, K Kato, H Yamada, Y Yamada, T Adachi, H Goto, N Ogasawara, A Futenma, M Kitano, H Miyai, A Fukatsu, K Hirano, S Kakumu, T Adachi, XL Wang, SL Marklund, P Nilsson, K Israelsson, I Schampi, M Peltonen, K Asplund, N Sakashita, Y Ando, SL Marklund, P Nilsson, K Tashima, T Yamashita, K Takahashi, CGP Mathew, Walker J, B Budowle, R Chakraborty, AM Giusti, AJ Eisenberg, RC Allen, DA Roff, P Bentzen, SL Church, JW Grant, EU Meese, JM Trent, M Caulfield, P Lavender, M Farral, P Nunroe, M Lawson, P Turner, AJI Clark, A Hingorani, MJ Brown, GF Van Landeghem, P Tabatabaie, V Kucinskas, N Saha, G Beckman, S Shimoda-Matsubayashi, Y Hattori, H Matsumine, A Shinohara, A Yoritaka, H Mori, T Kondo, M Chiba, Y Mizuno, P Jenner, S Melov, J Schneider, B Day, D Hinerfield, P Coscun, SS Mirra, ID Crapo, DC Wallace, T Adachi, H Yamada, Y Yamada, N Morihara, N Yamazaki, T Murakami, A Futenma, K Kato, K Hirano
Journal: BMC Medical Genetics (2001)
Abstract
gene in type 1 diabetic patients with (n = 82) and without DN (n = 84). gene were significantly lower in DN patients than in diabetic subjects without DN. In contrast, the Val allele (49.4% vs. 31.5%, p < 0.002) and the Val/Val genotype (15.9% vs. 2.4%, p < 0.01) were significantly more frequent in the DN patients than in the control group. gene was associated with DN in a Russian population
Background
gene in type 1 diabetic patients with (n = 82) and without DN (n = 84).
Results
gene were significantly lower in DN patients than in diabetic subjects without DN. In contrast, the Val allele (49.4% vs. 31.5%, p < 0.002) and the Val/Val genotype (15.9% vs. 2.4%, p < 0.01) were significantly more frequent in the DN patients than in the control group.
Conclusions
gene was associated with DN in a Russian population
Background
].
]. Antioxidant enzymes may protect against the rapid onset and progression of diabetic neuropathy (DN) by reducing the excess of both OFR and peroxide. Defects and mutations in the genes encoding these enzymes may therefore lead to suspectibility to DN.
Superoxide dismutase (SOD) is the key antioxidant enzyme involved in the detoxication of superoxide radicals. SOD is a metalloprotein and its manganese form (Mn-SOD) is present in mitochondria. Two other forms containing cooper and zinc (CuZn) have cytoplasmic or extracellular (EC-SOD) location.
].
].
].
genes.
Subjects
In this study, 88 healthy Russian donors selected at random (59 males and 29 females, mean age 28.3 ± 8.4 years, mean ± SEM) were examined. Healthy subjects had no autoimmune, cardiovascular, or other diseases. All study participants lived in Moscow or the Moscow region. Blood samples were collected in the Department of Endocrinology and Diabetology of the Russian Academy for Advanced Medical Studies. This study was approved by the Academy Review Board and was carried out in accordance with the principles of the second Helsinki Declaration. Informed consent was obtained from all subjects before participation in this study.
.
Clinical characteristics of the patients
percentage of patients
Genomic DNA isolation and genotyping of Mn-SOD
gene, PCR primers SOD2-58F 5'-AAGCTCCTCCCATTATCTAATAGC-3' and SOD2-58R 5'-TCAGTGCAGGCTGAAGAGAT-3' were used. PCR was carried out in a PHC-2 thermal cycler (Techne, UK) with 35 cycles of denaturation for 1 min at 94°C, annealing for 1 min at 55°C (Ile58Thr) or 60°C (Ala(-9)Val), and extension for 1 min at 72°C.
].
Statistical analysis
polymorphisms and DN.
The Ala(-9)Val polymorphism of the Mn-SOD gene
).
I; 100-, 82- and 60-bp DNA fragments are shown.
= 2.0976 and G-statistic = 2.1149, p = 0.3930 ± 0.0154).
Allele and genotype distribution of the Ala(-9)Val SOD2 and Arg213Gly SOD3 polymorphic markers in healthy subjects
gene is associated with neuropathy in type 1 diabetes mellitus. The Ala allele (odds ratio = 0.48, 95% CI; 0.31–0.74) and the Ala/Ala genotype (odds ratio = 0.34, 95% CI; 0.17–0.66) are associated with lower risk of DN development in than the Val allele (odds ratio = 2.09, 95% CI; 1.35–3.24) and the Val/Val genotype (odds ratio = 5.10, 95% CI; 1.77–14.69).
Allele and genotype distribution of the Ala(-9)Val SOD2 polymorphic marker in type 1 diabetic patients with and without neuropathy
= 0.00657).
The Ile58Thr polymorphism of the Mn-SOD gene
32I. If codon 58 is ACA (Thr allele) the amplified product not cleaved by this enzyme.
gene and DN was observed in type 1 diabetic patients.
The Arg213Gly polymorphism of the EC-SOD gene
).
I; 90- and 76-bp DNA fragments are shown.
gene is not associated with nerve lesions in type 1 diabetes mellitus.
Allele and genotype distribution of the Arg213Gly SOD3 polymorphic marker in type 1 diabetic patients with and without neuropathy
Discussion and Conclusions
].
].
].
].
]. This observation provides future evidence for the involvement of the SOD2 gene in neuropathology.
]. Thus, older people with genetic defects in the four-helix bundle tetrameric interface of Mn-SOD may be especially prone to degenerative diseases.
].
Finally, we have no comparative data concerning the role of genetic factors directly related to oxidative stress in DN formation and progression. It would be of value to compare our findings with those of similar association studies in other populations.
Pre-publication history
The pre-publication history for this paper can be accessed here:
Acknowledgements
We thank Dr. I.A. Strokov for the collection of blood samples.
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